Stand up on your 2 legs with your 2 arms by your side and close your eyes. Now touch your nose with your left index finger and then your right index finger. If you have done that successfully within 20mm, congratulations! You have passed the field sobriety test. This test is used by American police officers to check for alcohol intoxication. If you’re intoxicated, your proprioception becomes impaired and you have difficulty locating your limbs in space relative to their noses. Proprioception comes from the Latin proprius, meaning "one's own", "individual", and capio, capere meaning “to take or grasp”. It refers to the sense of the relative position of one's own parts of the body and strength of effort being employed in movement. In humans, proprioception is provided by proprioceptors in skeletal striated muscles i.e. Muscle Spindles, tendons i.e. Golgi Tendon Organs and the fibrous membrane in joint capsules. This is different to exteroception, which refers to perception of the outside world, and interoception, which refers to perception of pain, hunger etc. and the movement of internal organs. Your brain integrates proprioceptive and vestibular information into its overall sense of body position, movement, and acceleration. The term kinaesthesia, which strictly means movement sense, is inconsistently used by psychologists and neuroscientists.
Whenever I sit in a public place like a train station or a shopping centre, I would notice scores of people walking and running in various directions and speeds: north, south, east, west, fast or slow. Their eyes were focused at a particular object or a scene like a friend or the next step towards their desired destination. This made me wonder why we move the way we do? In Bob Dylan’s song “Mississippi”, he sings “everybody got to move somewhere.” But why though? Are we constantly in motion due to a fatal flaw in our make-up? Is motion a neurotic aversion to standing still? According to Matt Wilkinson, author of Restless Creatures: The Story of Life in Ten Movements, he doesn’t think so and believes the reason is more significant. He states movement is a human ability and the driving force of evolution on Earth. From the beginning of life on Earth, the early organisms possessed the ability to explore their environment and move from place to place in order to access essential resources their competitors couldn’t. If a mishap befell them, their ability to move increased their chances of survival. It’s evidence locomotion dominated the evolution of life and continues to do so as you read this. Some organisms like corals and plants are static for a majority of their lifetimes. However, sometime in their life cycle, they experience a motile phase. This highlighted the significant benefits of motility.
- But how are you actually moving your own body?
- How can you consciously move your own limbs and appendages to walk, run, etc.?
- Are you commanding your own movements or is there a hidden driver of movement?
https://en.wikipedia.org/wiki/Motor_cortex
A brain region called the Motor Cortex, located in your Cerebrum, is involved in planning, control and execution of voluntary movements. Classically, the Motor Cortex is part of the Frontal Lobe located in the Posterior Precentral Gyrus immediately anterior to the Central Sulcus. It is divided into 3 areas:
- Primary Motor Cortex = This region is located on the Anterior Paracentral Lobule of the Medial surface. It mainly contributes to generating neural impulses that pass down to the spinal cord and control the execution of movement. However, some of the other motor areas in the brain also play a role in this function. The Primary Motor Cortex contains cells with giant cell bodies known as “Betz Cells”, first discovered by Alfred Walter Campbell. They account for about 2-3% of the projections from the cortex to the spinal cord, or about 10% of the projections from the primary motor cortex to the spinal cord. The specific function of Betz Cells that distinguishes them from other output cells of the motor cortex remains unknown. However they continue to be used as a marker for the primary motor cortex.
- Premotor Cortex = This region is anterior to the primary motor cortex. It is responsible for some aspects of motor control, including the preparation for movement, the sensory guidance of movement, the spatial guidance of reaching, or the direct control of some movements emphasising control of proximal and trunk muscles of the body. The Premotor Cortex is divided into 4 sections: Upper / Dorsal Premotor Cortex (PMD) and Lower / Ventral Premotor Cortex (PMV) . Each of these sections is further divided into the Rostral (r) Premotor Cortex (toward the front of the brain) and the Caudal (c) Premotor Cortex (toward the back of the brain). The sections are PMDr (Field, F7), PMDc (F2), PMVr (F5) and PMVc (F4).
— PMDr plays a role in learning to associate arbitrary sensory stimuli with specific movements or learning arbitrary response rules. This a resemblance of the Premotor Cortex rather than other motor cortex fields. When PMDr neurons are electrically stimulated, it evoked eye movements and neuronal activity in the same region can be modulated by eye movements.
— PMVc plays a role in sensory guidance of movement. Neurons in this region respond to tactile, visual, and auditory stimuli. These neurons are quite sensitive to objects in the space immediately surrounding the body, known as the peripersonal space. When PMVc neurons are electrically stimulated, it caused an apparent defensive movement as if the organism is protecting its own body surface from physical harm or injury. This suggests it may be part of a a larger circuit for maintaining a margin of safety around the body and guiding movement with respect to nearby objects.
— PMVr plays a role in shaping the hand during grasping and in interactions between the hand and the mouth. When some parts of PMVr are electrically stimulated on a behavioural time scale, it evoked a complex movement involving the hand moving to the mouth, closing in a grip, orienting in a way in order for the grip to face the mouth, the neck turning to align the mouth to the hand, and the mouth opening. In addition, Rizzolatti and colleagues discovered Mirror Neurons in PMVr of monkey brains. These neurons were active when the monkey grasped an object, as well as watching an experimenter grasp an object in the same way. This infers mirror neurons are both sensory and motor neurons. They are proposed o be a basis for understanding the actions of others by internally imitating the actions using one’s own motor control circuits.
- Supplementary Area (SMA) = This region is on the midline surface of the hemisphere anterior to the primary motor cortex. It’s proposed its functions include internally generated planning of movement, the planning of sequences of movement, and the coordination of both sides of the body i.e. bi-manual coordination. According to Penfield, each neuron in the SMA may influence many muscles, many body parts on both sides of the body to suggest an extensive overlapping motor map. The SMA projects directly to the spinal cord and may play some direct role in the control of movement. Based on electrical stimulation of SMA, the movements evoked suggests the SMA may have evolved in primates as a specialist as part of the motor repertoire involving climbing and other complex locomotion. Based on the pattern of projections to the spinal cord, it has been suggested that another set of motor areas may lie adjacent to the SMA, on the medial (or midline) wall of the hemisphere. These medial areas are termed the cingulate motor areas, but their functions are not yet understood.
- Posterior Parietal Cortex = It’s often regarded as an association cortex rather than a motor cortical area. It is thought to be responsible for transforming multi-sensory information into motor commands, and some aspects of motor planning, as well as as non-motor functions.
- Primary Somatosensory Cortex = Especially the 3a region, lying directly against the motor cortex, this region is considered to be functionally associated with motor control circuitry.
https://en.wikipedia.org/wiki/Cortical_homunculus
The motor cortex map is regarded as a simple view that neurons in motor cortex control movement by a feedforward direct pathway. i.e. Neuron from Motor Cortex —> Spinal Cord —> Motor Neuron —> Muscle —> Contraction. The greater the activity in motor cortex, the stronger the muscle force. Each point in motor cortex controls a muscle or a small group of related muscles. This description is only partly correct. Most neurons in the motor cortex that project to the spinal cord synapse on interneuron circuitry in the spinal cord, not directly onto motor neurons. One theory describes the direct, cortico-motoneuronal projections being a specialisation that allows for the fine control of the fingers.
This is called a cortical homunculus, which is a distorted representation of the human body based on a neurological “map” of the areas and proportions of the human brain dedicated to processing motor or sensory functions, for different parts of the body. Homunculus comes from the Latin for “little man”, which was first used in alchemy and folklore before scientific literature began using it. Also known as “cortex man”, a cortical homunculus illustrates the concept of heuristically representing the body inside the brain. Nerve fibres from the spinal cord terminate in various areas of the Parietal Lobe in the Cerebral Cortex, which forms a representational map of the body. This concept was originally developed by Dr. Wilder Penfield and his co-investigators Edwin Boldrey and Theodore Rasmussen, but they weren’t the first scientists who attempted to objectify human brain function by means of a homunculus.
Along the length of the Primary Motor and Sensory cortices, the areas specialising in different parts of the body are arranged in an orderly fashion but not how one expects it to ordered. The toes are represented at the upper end (top) of the cerebral hemisphere. As you move down the hemisphere, progressively higher parts of the body are represented, assuming a faceless body and with their arms raised. Further down the cortex are the different areas of the face represented in approximately top-to-bottom order, rather than bottom-to-top as before. The homunculus is split in half, with motor and sensory representations for the left side of the body on the right side of the brain, and vice versa. It’s important to note that the amount of cortex devoted to any given body region is not proportional to that body region's surface area or volume, but rather to how richly innervated that region is. Body areas with more complex and/or more numerous sensory or motor connections are represented larger in size in the homunculus, while those with less complex and/or less numerous connections are represented smaller in size. The resulting image is that of a distorted human body, with disproportionately huge hands, lips, and face. In the sensory homunculus, an area beneath the areas managing sensation for the teeth, gums, jaw, tongue, and pharynx is dedicated for intra-abdominal sensation. Sensory neural networks for the genitals is believed to situate at the very top end of the primary sensory cortex, beyond the area for the toes. Recently, research suggests the possibility of two different cortical areas for the genitals, with one area dealing with erogenous stimulation and the other dealing with non-erogenous stimulation.
https://en.wikipedia.org/wiki/Basal_ganglia
In neural development, the human Central Nervous System is classified based on the original 3 primary vesicles from it develops. These vesicles are initially called Prosencephalon, Mesencephalon and Rhombencephalon, arranged in rostral to caudal (from head to tail) orientation. during the normal development of the Neural Tube in the Embryo. Later in development of the nervous system each section itself turns into smaller components: Prosencephalon divides into Telencephalon and Diencephalon, Rhombencephalon divides into Metencephalon and Myelencephalon, whilst the Mesencephalon remains as it is. Then neural cells migrate tangentially to form the basal ganglia are directed by the lateral and medial ganglionic eminences. The following table demonstrates this developmental classification and traces it to the anatomic structures found in the basal ganglia. The structures relevant to the basal ganglia are shown in bold.
(1) Prosencephalon:
- Telencephalon —> On each side of the brain: Cerebral cortices, Caudate, Putamen, Hypothalamus
- Diencephalon —> Globus pallidus, Ventral Pallidum, Thalamus, Subthalamus, Epithalamus, Subthalamic nucleus
(2) Mesencephalon —> Midbrain: Substantia Nigra Pars compacta (SNc), Substantia Nigra Pars reticulata (SNr)
(3) Rhombencephalon:
- Metencephalon —> Pons and Cerebellum
- Myelencephalon —> Medulla
Located at base of the forebrain is a group of subcortical nuclei called the Basal Ganglia (Basal Nuclei). The Basal Ganglia is strongly interconnected with the Cerebral Cortex, Thalamus, and Brainstem, as well as other brain areas. It’s associated with a variety of functions including: control of voluntary motor movements, procedural learning, habit learning, eye movements, cognition and emotion.
The basal ganglia form a fundamental component of the Cerebrum. In contrast to the cortical layer lining surface of the forebrain, the basal ganglia are a collection of distinct masses of grey matter lying deep in the brain not far from the junction of the Thalamus. Furthermore, they are situated beside and surround the Thalamus. Like most parts of the brain, the basal ganglia consist of left and right sides that are virtual mirror images of each other. Anatomically speaking the Basal Ganglia are divided into 4 distinct structures:
A. Striatum: Dorsal (Caudate Nucleus + Putamen) & Ventral (Nucleus Accumbens + Olfactory Tubercle)
= This subcortical structure is divided into the Dorsal Striatum and Ventral Striatum.
— The Dorsal Striatum receives excitatory glutamatergic inputs from the Cortex and dopaminergic inputs from the Substantia Nigra Pars compacta, whilst the Ventral Striatum receives excitatory glutamatergic inputs from areas of the limbic system and dopaminergic inputs from the VTA (Ventral Tegmental Area) via the mesolimbic pathway.
— The Dorsal Striatum is considered to be involved in sensorimotor activities, whereas the Ventral Striatum is thought to play a role in reward and other limbic functions.
— The Dorsal Striatum is divided into the Caudate and Putamen by the Internal Capsule while the Ventral Striatum is divided into the Nucleus Accumbens and Olfactory Tubercle. The Caudate connects to 3 other brain regions:
— The head projects to the Prefrontal Cortex, Cingulate Cortex and Amygdala.
— The body and tail differentiate between the Dorsolateral Rim and Ventral Caudate, then project to the sensorimotor and limbic regions of the Striatum respectively. Striatopallidal fibres connect the Striatum to the Pallidus.
The Striatum is mainly composed of medium spiny neurons that secrete an inhibitory neurotransmitter called GABA. These GABAergic neurons project project to both the external (lateral) Globus Pallidus and internal (medial) Globus Pallidus, as well as the Substantia Nigra Pars reticulata. These projections are primarily secrete Dopamine but it also secretes Enkaphlin, Dynorphin and Substance P. The Striatum also contains nitrergic interneurons that secrete Nitric Oxide as a neurotransmitter, tonically active cholinergic interneurons that secrete Acetylcholine, neurons expressing Parvalbumin and neurons expressing Calretinin.
B. Pallidum: (Globus Pallidus + Ventral Pallidum)
= This brain region divides into a large structure called the Globus Pallidus (“pale globe”) and a smaller ventral extension called the Ventral Pallidum. The Globus Pallidus appears as a compact neural mass, but is in fact divided into two functionally distinct parts, called the internal (i) / medial and external (e) / lateral segments, abbreviated GPi and GPe. Both segments contain primarily inhibitory GABAergic neurons, with each segment participating in distinct neural circuits. The GPe receives inputs mainly from the striatum, and projects to the Subthalamic Nucleus, whilst GPi receives signals from the Striatum via the "direct" and "indirect" pathways, suggesting pallidal neurons operate using a disinhibition principle. These neurons fire at steady high rates in the absence of input, and inputs from the Striatum cause them to pause or reduce their rate of firing. The disinhibition principle refers to pallidal neurons themselves produce inhibitory effects on their targets, eliciting the net effect of striatal input to the pallidum. This causes a reduction of the tonic inhibition exerted by pallidal cells on their targets (disinhibition) with an increased rate of firing in the targets.
C. Substantia Nigra (Pars compacta + Pars reticulata)
= This brain region is located in the midbrain, composed mainly of grey matter. It is divided into the Pars compacta (SNc) and Pars reticulata (SNr), and these 2 regions often work in unison with each other, and the SNr-GPi complex inhibits the thalamus. SNc produces a neurotransmitter called Dopamine, which plays a significant role in maintaining balance in the striatal pathway.
D. Subthalamic Nucleus (STN)
= This brain region is a diencephalic portion composed of grey matter, and it is the only portion of the Ganglia that produces Glutamate. The role of the STN is to stimulate stimulate the SNr-GPi complex as part of the indirect pathway. TheSTN receives inhibitory input from GPe and, in response, sends excitatory input to the GPi.
— Red = Excitatory glutamatergic pathways
— Blue = Inhibitory GABAergic pathways
— Magenta = Modulatory Dopaminergic pathways
(a) Direct Pathway: This pathway originates in the Dorsal Striatum, which inhibits the GPi and SNr. This results in a net disinhibition or excitation of the thalamus. It consists of medium spiny neurons (MSNs) that express Dopamine Receptor D1, Muscarinic Acetylcholine Receptor M4 and Adenosine Receptor A1. It’s theorised to facilitate motor actions, timing of motor actions, gating of working memory and motor responses to specific stimuli.
(b) Indirect Pathway: This pathway originates in the Dorsal striatum and inhibits the GPe, which results in disinhibition of the GPi which is then free to inhibit the Thalamus. It consists of MSNs that express Dopamine Receptor D2, Muscarinic Acetylcholine Receptor M1, and Adenosine Receptor A2a. It has been proposed to result in global motor inhibition(inhibition of all motor activity), and termination of responses. Another proposed indirect pathway involves cortical excitation of the STN, which results in direct excitation of the GPe, and inhibition of the thalamus. It then results in inhibition of specific motor programs based on associative learning. Combining these indirect pathways results in a hyperdirect pathway that inhibits basal ganglia inputs besides one specific focus propossed as part of the centre-surround theory. This hyperdirect pathway is suggested as a way to inhibit premature responses, or globally inhibit the basal ganglia in order for more specific top down control directed by the cortex. However the projections that make up these pathways are still being debated amongst researchers and neuroscientists. Some claim that all pathways directly antagonise each other in a "push pull" fashion, while others support the center surround theory. This refers to which one focused input into the cortex is protected by inhibition of competing inputs by the rest of the indirect pathways.
1. Motor Loop:
= This pathway involves projections from the Supplementary Motor Area, Arcuate Motor Area, Motor Cortex and Somatosensory Cortex into the Putamen. The Putamen then projects into the ventrolateral GPi and caudolateral SNr, which then projects into the Cortex through the ventralis lateralis pars medialis and ventralis lateralis pars orialis.
2. Oculomotor Loop:
= This pathway involves projections from the frontal eye fields, the Dorsolateral Prefrontal Cortex (DLPFC), into the caudal dorsomedial GPi and ventrolateral SNr. Then it loops back into the cortex through the lateral ventralis anterior pars magnocellularis(VAmc).
3. Cognitive/associative Pathway #1:
= It’s theorised this pathway begins from the DLPFC, then projects into the dorsolateral caudate. This is followed by a projection into the lateral dorsomedial GPi, and rostral SNr before projecting into the lateral VAmc and Medial Pars Magnocellularis.
4. Cognitive/associative Pathway #2:
= It’s theorised this pathway is circuit projecting from the lateral Orbitofrontal Cortex, the Temporal Gyrus, and Anterior Cingulate Cortex (ACC) into the Ventromedial Caudate. This is followed by a projection into the lateromedial GPi, and rostrolateral SNr before looping into the cortex via the medial VAmc and Medial Magnocellularis.
5. Limbic Loop:
= This pathway involves projections from the ACC, Hippocampus, Entorhinal Cortex, and Insula into the Ventral striatum. Then it projects into the rostrodorsal GPi, Ventral Palladium and rostrodorsal SNr. Finally it’s followed by a loop back into the cortex through the posteromedial part of the Medial Dorsal Nucleus. However, more subdivisions of (up to 20,000) loops have been proposed.
The basal ganglia contains afferent neurons that release Glutamate and efferent neurons that release GABA, along with with modulatory pathways that utilise Acetylcholine and dopaminergic neurons as part of the limbic pathways originating in the Ventral Tegmental Area (VTA) and Substantia Nigra. Other neuropeptides found in the basal ganglia include Substance P, Neurokinin A, Cholecystokinin, Neurotensin, Neurokinin B, Neuropeptide Y, Somatostatin, Dynorphin, Enkephaline. Other neuromodulators found in the basal ganglia include Nitric Oxide, Carbon Monoxide and Phenylethylamine.
There are 4 proposed functions of the basal ganglia:
— Eye movements = This function is controlled by an extensive neural network converging on a region in the midbrain called the Superior Colliculus (SC). The SC is a layered structure that forms 2D retinotopic maps of visual space within its layers. A “bump” of neural activity in the deep layers of the SC drives an eye movement directed toward the corresponding point in space. SC receives inhibitory projections from the Substantia Nigra Pars reticulata (SNr). Neurons in the SNr usually fire continuously at high rates, but “pause” at the onset of an eye movement, which momentarily releases the inhibition from the SC. Neurons in parts of the Caudate Nucleus also demonstrate activity in relation to eye movements. Since a majority of Caudate cells fire at very low rates, this activity almost always shows up as an increase in firing rate. Thus, we can conclude that eye movements begin with activation of neurons in the caudate nucleus, which inhibits the SNr via the direct GABAergic projections, which in turn disinhibits the SC. I’ll discuss eye movements in further detail later on.
— Motivation = In experiments involving rodents, it’s discovered a link between extracellular Dopamine in the basal ganglia to motivational states, Higher Dopamine levels associate with satiated “euphoria”, medium levels associate with seeking and low levels associate with aversion. In limbic circuits, increased extracellular Dopamine levels results in inhibition of the Ventral Pallidum, Entopeduncular nucleus, and SNr, which disinhibits the Thalamus. This model of direct D1, and indirect D2 pathways may explain why selective agonists of each receptor are not rewarding, as activity at both pathways is required for disinhibition. When the Thalamus is disinhibited, it leads to activation of Prefrontal Cortex and Ventral Striatum, which are selective for increased D1 Receptor activity leading to reward. I’ll delve deeper in motivation later on.
— Decision making = 2 models have been proposed for the basal ganglia’s role in this function. The first model suggests that actions are generated by a "critic" in the Ventral Striatum and estimates its value, meanwhile actions are carried out by an "actor" in the Dorsal Striatum. The second model suggests the basal ganglia acts as a selection mechanism, where actions are generated in the cortex and are selected based on context by the basal ganglia. The CBGTC (Cortico-Basal Ganglia-Thalamo-Cortical) loop is also involved in reward discounting, because its firing activiteis increases when an organism experiences an unexpected or greater than expected reward. One review supported the idea that the cortex was involved in learning actions regardless of their outcome, while the basal ganglia was involved in selecting appropriate actions based on associative reward and trial-and-error learning. I’ll delve deeply in the decision making in another post.
— Working memory = There’s a theory proposing the basal ganglia’s role in gating which information enters our working memory. One theory hypothesised that the that the direct pathway (Go, or excitatory) transmits information into the PFC, where it stays independent of the pathway. Another theory proposes that the direct pathway needs to continuously reverberate for information to stay in the PFC. In a direct push-pull antagonism with the direct pathway, the shorter indirect pathway has been theorised to close the gate to the PFC. Together these mechanisms regulate working memory focus and I’ll dig deeper into the details in another post.
https://en.wikipedia.org/wiki/Motor_neuron
Your motor cortex, brainstem and spinal cord contains the cell bodies of motor neurons (motoneurons), whose axons project to or outside the spinal cord to directly / indirectly control effector organs such as muscles and organs. In embryonic development, motoneurons begin to develop early and motor function continues to develop well into childhood. In the neural tube, cells are given specific instructions to be in either the rostral-caudal axis or ventral-dorsal axis. By week 4, axons of motoneurons begin to appear from the ventral region of the ventral-dorsal axis, also called the basal plate. This homeodomain is known as the motor neural progenitor domain (pMN). Transcription factors like Pax6, OLIG2, Nkx-6.1 and Nkx-6.2 are regulated by Sonic Hedgehog (Shh), The OLIG2 gene promotes Ngn2 gene expression, which causes cell cycle exiting and promotion of further transcription factors associated with motor neuron development. Further specification of motoneurons occurs when Retinoic Acid, Fibroblast Growth Factor, Wnts and TGFb, are integrated into various Hox transcription factors, 13 of them in total. Along with the signals, Hox transcription factors determine whether a motor neuron will be more rostral or caudal in character. In the spinal column, Hox 4-11 sort motor neurons to 1 of the 5 motor columns.
1) The median motor column is present along the entire length of the spinal cord, targeting axial muscles.
2) The hypaxial motor column is located in the thoracic region of the spinal cord, targeting the body wall muscles.
3) The preganglionic motor column is also located in the thoracic region of the spinal cord, targeting the sympathetic ganglia.
4) The lateral motor column is located in the brachial and lumbar regions of the spinal cord, which further divide into medial and lateral domains. It targets muscles of the limbs.
5) The phrenic motor column is located in the cervical region of the spinal cord, targeting the diaphragm.
(A) Upper Motor Neurons:
They originate in the motor cortex located in the Precentral Gyrus. The cells that make up the primary motor cortex are called Betz Cells, a type of pyramidal cell, whose axons descend from the cortex to form the corticospinal tract. Nerve tracts are bundles of axons as white matter, carrying action potentials to their effectors. In the spinal cord, these descending tracts carry impulses from different regions. This is where lower motor neurons originate from nerve tracts. There are 7 major descending motor tracts in the spinal cord:
— Lateral corticospinal tract
— Rubrospinal tract
— Lateral reticulospinal tract
— Vestibulospinal tract
— Medial reticulospinal tract
— Tectospinal tract
— Anterior corticospinal tract
They originate in the spinal cord and directly / indirectly innervate effector targets, which often vary. In the somatic nervous system, the target will often be a muscle fibre. There are 3 primary categories lower motor neurons, which are further divided in sub-categories:
i. Somatic Motor Neurons:
= These neurons originate in the Central Nervous System, whose axons project to skeletal muscles such as muscles in the limbs, abdominal and intercostal muscles, which are involved in locomotion. There are 3 types of somatic motor neurons: α (alpha)-efferent neurons, β (beta)-efferent neurons, and γ-efferent neurons. They are called efferent because the flow of information originates from the CNS down to the periphery, and vice versa for afferent neurons.
— α-Motor Neurons = They innervate extrafusal muscle fibres, which are the main force-generating component of a muscle. Their cell bodies are located in the ventral horn of the of the spinal cord. On average, a single motor neuron may synapse with 150 muscle fibres. The combination of a motor neuron connecting to all of the muscle fibres is called a motor unit. Motor units are classified into 3 categories:
- Slow (S) Motor Units = Also called red fibres, they stimulate small slowly-contracting muscle fibres, which provide small amounts of energy. However, they are very resistant to fatigue, so they are used to sustain muscular contraction, such as keeping the body upright and maintain posture. They gain their energy via oxidative means, so they require oxygen.
- Fast Fatiguing (FF) Motor Units = Also called white fibres, they stimulate larger muscle groups, which apply large amounts of force but fatigue very quickly. They are often used for tasks that require large brief bursts on energy, such as jumping or sprinting. They gain their energy via glycolytic means and hence don't require oxygen.
- Fast Fatigue-resistant (FR) Motor Units = They stimulate moderate-sized muscles groups that don't react as fast as the FF motor units. However, they sustain force for a longer period, hence provide more force than S motor units.
In addition to voluntary skeletal muscle contraction, α-Motor Neurons also contribute to muscle tone, which involves a continuous continuous force generated by non-contracting muscle to oppose stretching. When the muscle is stretched, sensory neurons within muscle spindles detect the degree of stretch and send a signal to the CNS. The CNS activates α-motor neurons in the spinal cord, which cause extrafusal muscle fibres to contract and thereby resist further stretching. This process is called the stretch reflex.
— β-Motor Neurons = They innervate intrafusal muscle fibres of muscle spindles, with collaterals to extrafusal fibres. There are 2 types of β-Motor Neurons:
- Slow Contracting = These innervate extrafusal muscle fibres.
- Fast Contracting = These innervate intrafusal muscle fibres.
— γ-Motor Neurons = They innervate intrafusal muscle fibres within the muscle spindle to help regulate the sensitivity of the spindle to muscle stretching. When these motor neurons are stimulated, this causes contraction of intrafusal muscle fibers so that only a small stretch is required to activate muscle spindle sensory neurons and the stretch reflex. There are 2 types of γ-Motor Neurons:
- Static = These focus on Bag2 fibres and enhance stretch sensitivity.
- Dynamic = These focus on Bag1 fibres and enhance dynamic sensitivity.
— The regulatory factors of lower motor neurons size principle relates to the soma of the motor neuron. This restricts neurons with larger somas from receiving a larger excitatory signal in order to stimulate the muscle fibres it innervates. By reducing unnecessary muscle fibre recruitment, the body is able to optimise energy consumption. In recent animal study research, scientists have discovered a phenomenon called Persistent Inward Current (PIC), which involves a constant flow of ions such as Calcium and Sodium through channels in the soma. This suggests the post-synaptic neuron is being primed to receive an impulse before it arrives. A self-explanatory phenomenon called After-Hyperpolarisation (AHP) has been identified in slow motor neurons for a longer duration at higher intensity. Since slow muscle fibres can contract for longer, so it makes sense that their corresponding motor neurons fire at a slower rate.
ii. Special Visceral Motor Neurons:
Also known as branchial motor neurons, they are involved in facial expression, mastication, phonation, and swallowing. Associated cranial nerves include the Oculomotor, Abducens, Trochlear, and Hypoglossal nerves.
iii. General Visceral Motor Neurons:
They indirectly innervate cardiac muscle and smooth muscles of the viscera (i.e. the muscles of the arteries). They synapse onto neurons located in ganglia of the autonomic nervous system (sympathetic and parasympathetic), located in the peripheral nervous system (PNS), which themselves directly innervate visceral muscles as well as some gland cells. The motor command of skeletal and branchial muscles is monosynaptic (meaning it only involves 1 neuron) respectively, somatic and branchial, which then synapses onto the muscle. Meanwhile, the command of visceral muscles is disynaptic, meaning it involves 2 neurons: first one is the general visceral motor neuron in the CNS, which then synapses onto a ganglionic neuron in the PNS, which then synapses onto the muscle.
— In the Somatic Nervous System, somatic nerves release Acetylcholine.
— In the Parasympathetic Nervous System, both preganglionic and ganglionic nerves release Acetylcholine.
— In the Sympathetic Nervous System, preganglionic nerves release Acetylcholine, whereas ganglionic nerves release Noradrenaline with exceptions to sweat glands and certain blood vessels.
The contact between a motor neuron and a muscle fibre is a chemical synapse called a neuromuscular junction (NMJ). It’s a site where a motor neuron transmits a chemical signal to a muscle fibre to initiate muscle contraction. The sequence of events is as follows:
1. An action potential initiates in the cell body of the motor neuron, which is then propagated by saltatory conduction along its axon toward the NMJ.
2. Once the action potential reaches the terminal bouton, it causes a Calcium (Ca2+) ion influx into the terminal via voltage-gated Calcium channels.
3. This causes synaptic vesicles containing the neurotransmitter Acetylcholine to fuse with the plasma membrane of the pre-synaptic terminal, releasing Acetylcholine into the synaptic cleft between the motor neuron terminal and the NMJ of the skeletal muscle fibre.
4. Acetylcholine then diffuses across the synapse and binds to and activates Nicotinic Acetylcholine Receptors on the NMJ.
5.This opens the Nicotinic Receptors’ intrinsic Sodium / Potassium (Na+ / K+) channel, causing Na+ ions to enter and K+ ions to exit the neuron.
6. This results in reversing the Sarcolemma’s polarity and rapidly increasing the voltage i.e. depolarisation, from the resting membrane potential of -90mV to as high as +75mV during Na+ ion influx.
7. The membrane potential then hyperpolarises during K+ ion efflux and is then adjusted back to the resting membrane potential. This rapid fluctuation is called the end-plate potential.
8. In response to the end plate potential, the voltage-gated ion channels of the sarcolemma next to the end plate open.
9. These voltage-gated channels are semi-permeable to sodium and potassium and only allows one type of ion passively through.
10. This wave of ion movements generates the action potential, which spreads from the motor end plate in all directions.
11. If action potentials stop arriving, then Acetylcholine ceases to be released from the terminal bouton.
12. The remaining Acetylcholine in the synaptic cleft is either degraded by active Acetylcholinesterase or reabsorbed by the synaptic knob until none is left to replace the degraded Acetylcholine.
https://en.wikipedia.org/wiki/Muscle
Your body is home to hundreds of different muscles, estimated to be about 650. Muscle is a soft tissue made up of muscle cells containing protein filaments of Actin and Myosin that slide past one another. This causes muscle contraction that changes both the length and the shape of the cell. The main function of your muscles is to produce force and motion. They are primarily responsible for maintaining and changing posture, locomotion, movement of internal organs such as heart contraction and peristalsis to break down food in your digestive system.
There are 3 types of muscle tissue in vertebrates:
(A) Skeletal Muscle
https://en.wikipedia.org/wiki/Skeletal_muscle
This muscle type is a form striated muscle tissue that contracts under the voluntary control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibres known as tendons. Skeletal muscle are bundles (fascicles) of cells called muscle fibres. The fibres and muscles are surrounded by connective tissue layer called fasciae. Enclosing each muscle is a layer of connective tissue known as the Epimysium. Then enclosing each fascicle is another layer of connective tissue called the Perimysium. Finally enclosing each muscle fibre is a 3rd connective tissue layer called the Endomysium.
Muscle fibres are individual contractile units that form the main structure of muscle. Another group of cells called Myosatellite Cells are found between the basement membrane and sarcolemma of muscle fibres. These cells are normally quiescent but are activated by exercise or pathology to provide additional myonuclei for muscle atrophy or repair. During myogenesis, individual muscle fibres are formed from the fusion of several undifferentiated immature cells known as Myoblasts into long, cylindrical, multi-nucleated cells. Differentiation into this state is primarily completed before birth with the cells continuing to grow in size thereafter. When viewed under a microscope, skeletal muscle exhibits a distinctive banding patterns due to the arrangement of cytoskeletal elements n the cytoplasm of the muscle fibres. The principal cytoplasmic proteins, Myosin and Actin (also known as “thick” and “thin” filaments, respectively), are arranged in a repeating unit called a Sarcomere. Muscle contraction depends on the interaction between Actin and Myosin filaments. The cell membrane is called the Sarcolemma, whilst the cytoplasm is called the Sarcoplasm, where Myofibrils are found. The myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Unusually flattened myonuclei are pressed against the inside of the Sarcolemma. Mitochondria are situated between the myofibrils. Since the muscle fibre doesn’t contain a smooth endoplasmic cisternae, it contains a Sarcoplasmic Reticulum (SR) instead. The SR surrounds the myofibrils and holds a reserve of Calcium ions that are required to cause muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae, which cross the muscle fibre from 1 side to the other. . In between 2 terminal cisternae is a tubular infolding called a transverse tubule (T-tubule). T-Tubules are pathways to allow action potentials to signal the SR to release Calcium ions from its reserves, causing a muscle contraction. 2 terminal cisternae combine with a T-tubule to form a triad.
https://en.wikipedia.org/wiki/Muscle_architecture
When anatomists discuss muscle architecture, they refer to the physical arrangement of muscle fibres at the macroscopic level relative to the axis of force generation of the muscle that determines a muscle’s mechanical function. This axis is a hypothetical line from the muscle's origin to insertion. Several different muscle architecture types exist, which are listed below. Force generation and gearing vary depending on the different geometries of the muscle. Some parameters used in architectural analysis include muscle length (Lm), fibre length (Lf), pennation angle (θ), and physiological cross-sectional area (PCSA).
— Strap = These muscles are shaped like a strap or belt and have fibres running longitudinally to the direction of contraction. They have broad attachments, which allows the strap parallel muscle to shorten to about 40%-60% of its resting length. Strap muscles, such as laryngeal muscles, are theorised to control the fundamental frequency used in speech production, as well as singing. Another example is the Sartorius, which is the longest muscle in the human body.
— Fusiform = These muscles are wider and cylindrically shaped in the centre, which taper off at the ends. The overall shape is often referred to as a spindle. The line of action in this muscle type runs in a straight line between the attachment points, which are often tendons. Due to its shape, the force produced is focused on a small area. e.g. Biceps Brachii
— Fan-shaped = Known as convergent muscles, they have fibres converging at one end (typically at a tendon) and spreading over a broad area at the other end. An example of a fan-shaped muscle in humans is the Pectoralis Major. They have a weaker pull on the attachment site due to their broad nature. These muscles are versatile due to their ability to change the direction of pull depending on how the fibres are contracting.
b. PENNATE = These muscle fibres are oriented at an angle to the force-generating axis (known as the pennation angle) and are usually inserted into a central tendon. This means fewer sarcomeres are found in series, which result in a shorter fibre length. This allows for more fibres to be present in a given muscle; however, a trade-off exists between the number of fibres present and force transmission. Overall, more force is produced by pennate muscles compared to the force produced by parallel muscles. Since pennate fibres insert the tendon at an angle, the anatomical cross-sectional area cannot be used as in parallel fibered muscles. Therefore, the physiological cross-sectional area (PCSA) is used instead. Pennate muscles are further categorised as either:
— Unipennate = Fibres in these muscles are all oriented at the same angle (above zero) relative to the axis of force generation. This angle reduces the effective force of any individual fibre, as it effectively pulls off-axis. Because of this angle, more fibres can be packed into the same muscle volume, which increases the PCSA. In terms of force generation, this effect is known as ‘fibre packing’, which helps overcomes the efficiency loss of the off-axis orientation. The trade-off comes in overall speed of muscle shortening and in total excursion. Hence, this reduces overall muscle shortening speed compared to fibre shortening speed and the total distance of shortening. All of these effects are dependant on pennation angle, with greater angles increasing muscle force due to increased fibre packing and PCSA, but with greater losses in shortening speed and excursion. e.g. Vastus Lateralis.
— Bipennate = These muscles have fibres on two sides of a tendon. Their arrangements are essentially “V”s of fibres stacked on top of each other. Examples include the Stapedius muscle located in the middle ear of humans, Rectus Femoris and Quadriceps.
— Multipennate = These muscles have fibres arranged at multiple angles in relation to the axis of force generation. This category includes bipennate, convergent and multipennate muscles. While determining PCSA increases in difficulty in these muscle architectures, the same tradeoffs as listed above apply. Convergent muscles are arranged in the shape of a triangle or a fan, with wide origins and more narrow insertions. A wide variety of pennation angles allows for multiple functions. e.g. The Trapezius muscle is a prototypical convergent muscle that aids in both shoulder elevation and depression. Multipennate muscles possess a combination of bipennate or unipennate arrangements and convergent arrangements. e.g. Deltoid muscle.
https://en.wikipedia.org/wiki/Muscular_hydrostat
c. Muscular hydrostats function independently of a hardened skeletal system, because they are typically supported by a membrane of connective tissue which holds the volume constant. Retaining a constant volume enables the fibres to stabilise the muscle’s structure that would otherwise require skeletal support. Muscle fibres usually change the shape of the muscle by contracting along 3 general lines of action relative to the long axis: Parallel, Perpendicular and Helical. These contractions can apply or resist compressive forces to the overall structure.
https://en.wikipedia.org/wiki/Pennate_muscle
https://en.wikipedia.org/wiki/Physiological_cross-sectional_area
https://en.wikipedia.org/wiki/Architectural_gear_ratio
Muscle architecture directly influences force production via muscle volume, fibre length, fibre type and pennation angle. Muscle volume is determined by the cross-sectional area (CSA) , which it’s calculated as follows.
CSA = v / l
V = Muscle volume
l = Muscle length
In muscles a more accurate measurement of CSA is PCSA (physiological CSA), which takes fibre angle into account:
PCSA = (m*cos θ) / (l*ρ)
m = Muscle mass
θ = Fibre angle
l = Fibre length
ρ = Muscle density = m / v
In muscle physiology, PCSA is the area of the cross section of a muscle perpendicular to its fibres, generally at its largest point. This is not to be confused with anatomical cross-sectional area (ACSA), which is the area of the cross-section of a muscle perpendicular to its longitudinal axis. In non-pennate muscles, the fibres are parallel to the longitudinal axis, and therefore PCSA and ACSA coincide. PCSA increases as pennation angle and muscle length increases. In a pennate muscle, PCSA is always larger than ACSA. In a non-pennate muscle, it coincides with ACSA.
The total force exerted by the fibres in their oblique direction is directly proportional to PCSA. If the specific tension of the muscle fibres is known (i.e. force exerted by the fibres per unit of PCSA), then we can calculate it as:
Total Force = PCSA * (Specific Tension)
However, the only component of that force that can be used to pull the tendon in the desired direction is the true muscle force (also called tendon force, which is exerted along the direction of action of the muscle:
Muscle Force = (Total Force) * cos (θ)
The other component is orthogonal to the direction of action of the of the muscle: (Orthogonal Force) = (Total Force) * sin (θ). But instead of exerting force on the tendon, it simply squeezes the muscle, but pulling its aponeuroses toward each other. Note that that PCSA (and therefore the total fibre force) isn’t directly proportional to muscle mass or fibre length alone. Rather, the maximum (tetanic) force of a muscle fibre simply depends on its thickness (cross-section area) and type. By no means it depends on its mass or length alone. For instance, when muscle mass increases due to physical development during childhood, this may be only due to an increase in length of the muscle fibres, while fibre thickness (PCSA) or fibre type remains constant. In this case, an increase in mass does not produce an increase in force. Occasionally, the increase in mass associated with the increase in muscle thickness. Only in this case that it will elicit some effect on fibre force, but this effect will be proportional to the increase in thickness, not to the increase in muscle mass. For instance, in some stages of human physical development, the increase in mass may be due to both an increase in PCSA and in fibre length. In this case, muscle force does not increase as much as muscle mass does, due to the fact that mass increase is partly produced by a variation in fibre length, and fibre length has no effect on muscle force.
Another feature of pennate muscle is the Architectural (Anatomical) Gear Ratio (AGR). It’s commonly defined as the ratio between the longitudinal strain of the muscle and muscle fibre strain, but also defined as the ratio between muscle-shortening velocity and fibre-shortening velocity.
AGR = ε(x) / ε(f)
ε(x) = Longitudinal strain (or muscle-shortening velocity)
ε(f) = Fibre strain (or fibre-shortening velocity)
In fusiform muscles, the fibres are longitudinal, so longitudinal strain n is equal to fibre strain, hence AGR is always 1.
When the pennate muscle is activated, the fibres rotate as they shorten and pull at an angle. Pennate muscles fibres are oriented at an angle to the muscle’s line of action and rotate as they shorten to become more oblique such that a fraction of force directed along the muscle's line of action decreases throughout a contraction. Force output depends on the angle of fibre rotation, so changes in muscle thickness and the vector of change in thickness would vary, which is based upon the amount of force being produced. Due to the rotational motion, pennate muscles typically operate at low velocities, hence low shortening distance. The shortening velocity of the pennate muscle as a whole is greater than that of individual fibres, which then gives rise to a property of AGR. When a muscle fibre rotates, it decreases a muscle's output force but increases output velocity because it allows the muscle to function at a higher gear ratio (i.e. higher muscle velocity/fibre velocity).
AGR evaluates a relationship between the contractile velocity of an entire muscle to the contractile velocity of a single muscle fibre. It is determined by the mechanical demands of a muscle during movement. Changes in the pennation angle would allow for variable gearing in pennate muscles. Variations in pennation angle also influences whole-muscle geometry during muscle contraction. During the course of the movement, the degree of fibre rotation determines the cross-sectional area. This can result in increases of the thickness or width of the muscle.
A high AGR occurs when:
— The contraction velocity of the whole muscle is much greater than that of an individual muscle fibre, resulting in a AGR greater than 1.
— The same outcome also results in low force, high velocity contractions of the entire muscle.
— During contraction, the angle of pennation will increase, as well as an increase in muscle thickness, which is defined as the area between the aponeuroses of the muscle.
On the other hand, a low AGR occurs when:
— The contraction velocity of the whole muscle and individual fibres is approximately the same, resulting in an AGR of 1.
— Conditions that result in this outcome include high force and low velocity contraction of the whole muscle.
— The pennation angle typically shows little variation.
— The muscle thickness will decrease.
In adult animals, the skeletal muscle fibre-type phenotype is regulated by several several independent signalling transduction pathways. Those pathways include:
— Ras / Mitogen-activated Protein Kinase (MAPK) Pathway = This pathway links the motor neurons and signalling systems, which couples excitation and transcription regulation to promote the nerve-dependent induction of the slow program in regenerating muscle.
— Calcineurin = A Ca(2+) / Calmodulin-activated Phosphatase that is implicated in nerve activity-dependent fibre-type specification in skeletal muscle, which directly controls the phosphorylation state of the transcription factor NFAT. This allows for its translocation to the nucleus, leading to the activation of slow-type muscle proteins in cooperation with Myocyte Enhancer Factor 2 (MEF2) proteins and other regulatory proteins.
— Calcium/calmodulin-dependent Protein Kinase IV = This pathway is upregulated by slow motor neuron activity. This is possibly due to it amplifying the slow-type calcineurin-generated responses by promoting MEF2 Transactivator functions and enhancing oxidative capacity through stimulation of mitochondrial biogenesis. Contraction-induced changes in intracellular Calcium or Reactive Oxygen Species provide signals to diverse pathways like the MAPKs, Calcineurin and calcium/calmodulin-dependent protein kinase IV. This would activate transcription factors that regulate gene expression and enzyme activity in skeletal muscle.
— Peroxisome Proliferator γ Coactivator 1 (PGC-1(α), PPARGC1A) = A transcriptional coactivator of nuclear receptors that plays a role in regulating a number of mitochondrial genes involved in oxidative metabolism. PGC-1 directly interacts with MEF2 to synergistically activate selective slow twitch (ST) muscle genes and also serves as a target for Calcineurin signalling.
— Peroxisome Proliferator-activated Receptor δ (PPARδ) = This is a mediated transcriptional pathway involved in the regulation of the skeletal muscle fibre phenotype. When mice harbour an activated form of PPARδ, they display an “endurance” phenotype along with a coordinated increase in oxidative enzymes and mitochondrial biogenesis and an increased proportion of ST fibres.
Therefore, Calcineurin, calmodulin-dependent kinase, PGC-1α, and activated PPARδ form the basis of a signalling network via functional genomics that controls skeletal muscle fibre-type transformation and metabolic profiles that protect against insulin resistance and obesity.
During intense work, transitioning from aerobic to anaerobic metabolism requires rapid activation of several systems to ensure a constant supply of ATP for the working muscles. These changes include switching from fat-based to carbohydrate-based fuels, redistributing blood flow from non-working to exercising muscles, and removing several of the by-products of anaerobic metabolism, such as Carbon Dioxide and Lactic Acid. Some of these responses are controlled by transcriptional control of the fast twitch (FT) glycolytic phenotype. For instance, the Six1/Eya1 Complex (composed of members of Six protein family) helps the reprogramming of skeletal muscle from a ST glycolytic phenotype to an FT glycolytic phenotype
Recent research identified the Hypoxia-Inducible Factor 1-α (HIF1A) as a master regulator for the expression of genes involved in essential hypoxic responses that maintain ATP levels in cells. If HIF1A were ablated, it would increase the activity of rate-limiting enzymes of the Mitochondria. This indicates that the Citric Acid Cycle and increased Fatty Acid oxidation may be compensating for the reduced flow through the glycolytic pathway. However, hypoxia-mediated HIF-1α responses are also linked to the regulation of mitochondrial dysfunction through the formation of excessive reactive oxygen species in Mitochondria. Other pathways that could influence adult muscle include a transcription factor called Serum Response Factor (SRF), which is released from the structural protein Titin in the event of physical force inside a muscle fibre. This leads to altered muscle growth.
When a muscular action potential in the muscle fibre causes the myofibrils to contract, this initiates a process called excitation-contraction coupling. In skeletal muscle, excitation–contraction coupling relies on a direct coupling between key proteins, the Sarcoplasmic Reticulum (SR) Calcium release channel (known as the Ryanodine Receptor, RyR) and voltage-gated L-Type Calcium channels (known as Dihydropyridine Receptors, DHPRs). DHPRs are located on the sarcolemma, while the RyRs reside across the SR membrane. Excitation–contraction coupling predominately takes place at a triad consisting of a transverse tubule and two SR regions containing RyRs in close apposition.
1. Depolarisation of skeletal muscle cell results in a muscle action potential, which spreads across the cell surface and into the muscle fibre's network of T-Tubules.
2. This depolarised the inner portion of the muscle fibre.
3. This activates Dihydropyridine receptors in the terminal cisternae, which are in close proximity to RyR in the adjacent SR.
4. The activated Dihydropyridine receptors then physically interact with and activate RyRs via foot processes (involving conformational changes that allosterically activates the RyRs).
5. As the ryanodine receptors open, Ca2+ ions are released from the SR into the local junctional space.
6. They then diffuse into the bulk cytoplasm to cause a Calcium spark. Note that the SR has a large Calcium buffering capacity partially due to a Calcium-binding protein called Calsequestrin.
7. The near synchronous activation of thousands of Calcium sparks by the action potential causes a cell-wide increase in Calcium levels, which gives rise to the upstroke of the Calcium transient.
8. The Ca2+ ions released into the cytosol then binds to Troponin C by the Actin filament.
9. This allows crossbridge cycling, producing force, hence motion.
10. The Sarco/endoplasmic Reticulum Calcium-ATPase (SERCA) actively pumps Ca2+ ions back into the SR.
11. At Ca2+ ions levels decline back to resting levels, the force produces starts to decline and muscle relaxation occurs.
https://en.wikipedia.org/wiki/Sliding_filament_theory
The sliding filament theory was originally conceived by Hugh Huxley in 1953 but it wasn’t until 1954 that the theory was independently introduced by 2 research teams. One team consisted of Andrew F. Huxley and Rolf Niedergerke from the the University of Cambridge, and other team consisted of Hugh Huxley and Jean Hansen from the Massachusetts Institute of Technology. On 22 May 1954, the sliding filament theory was born from 2 consecutive papers published in Nature under the common theme “Structural Changes in Muscle During Contraction”. Though both conclusions were fundamentally similar, each of their underlying experimental data and propositions were somewhat different.
The first paper, written by Andrew Huxley and Rolf Niedergerke, is titled "Interference microscopy of living muscle fibres”. It was based on their study of frog muscle using an interference microscope, which Andrew Huxley developed for this purpose. According to A.Huxley and Niedergerke:
— The I-Bands are composed of Actin filaments and the A-bands principally of myosin filaments.
— During contraction, the Actin filaments move into the A bands between the myosin filaments.
The second paper, written by Hugh Huxley and Jean Hanson, is titled "Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation”. It was based based on their study of rabbit muscle using phase contrast and electron microscopes. According to H. Huxley and Hanson:
I. The backbone of a muscle fibre contains Actin filaments, which extend from Z-line up to one end of H-Zone, where they are attached to an elastic component which they named S-filament.
II. Myosin filaments extend from one end of the A-band through the H-zone up to the other end of the A-band.
III. Myosin filaments remain in relatively constant length during muscle stretch or contraction.
IV. If Myosin filaments contract beyond the length of A-band, their ends fold up to form contraction bands.
V. Myosin and Actin filaments lie side-by-side in the A-band and in the absence of ATP they do not form cross-linkages.
VI. During stretching, only the I-bands and H-Zone increase in length, while A-bands remain the same.
VII. During contraction, Actin filaments move into the A-bands and the H-Zone is filled up, the I-bands shorten, the Z-line comes in contact with the A-bands.
VIII. The possible driving force of contraction is the actin-myosin linkages which depend on ATP hydrolysis by the Myosin.
Initially this theory was refuted for a few decades. However it wasn’t until 1972 after a conference at the Cold Spring Harbour Laboratory, that the sliding filament theory was deliberated, and accepted by the scientific community. The sliding filament theory explains the mechanism of muscle contraction based on muscle proteins that slide past each other to generate movement. On 20 June 1969, Hugh Huxley published his theory in Science titled “The Mechanism of Muscular Contraction”. He explains filament sliding occurs by cyclic attachment and detachment of Myosin on Actin filaments. When the Myosin pulls the Actin filament towards the centre of the A-band, detaches from Actin and creates a force (stroke) to bind to the next actin molecule, muscle contraction occurs. This idea was subsequently proven in detail, and is more appropriately known as the cross-bridge cycle.
Crossbridge cycling describes a sequence of of molecular events underlying the sliding filament theory. It’s a Myosin projection that consists of 2 Myosin heads extending from the thick filaments. Each Myosin head has 2 binding sites: 1 for ATP and another for Actin.
1. When ATP binds to the Myosin head, the Myosin detaches from Actin, thereby allowing Myosin to bind to another Actin molecule.
2. Once attached, ATP is hydrolysed by Myosin, which uses the released energy to move into the "cocked position”, whereby it binds weakly to a part of the Actin binding site.The remainder of the Actin binding site is blocked by Tropomyosin.
3. With the ATP hydrolysed, the cocked myosin head now contains ADP + Pi (Phosphate).
4. Then, 2 Ca2+ ions bind to Troponin C on the Actin filaments.
5. The Troponin-Ca2+ complex causes Tropomyosin to slide over and unblock the remainder of the Actin binding site.
6. This would allow the 2 Myosin heads to close and Myosin to bind strongly to Actin.
7. The Myosin head then releases the inorganic Phosphate and initiates a power stroke, which generates a force of 2 pN.
8. The power stroke moves the Actin filament inwards, thereby shortening the Sarcomere.
9. Myosin then releases ADP but still remains tightly bound to Actin.
10. At the end of the power stroke, ADP is released from the Myosin head, leaving Myosin attached to actin in a rigour state until another ATP binds to Myosin.
11. A lack of ATP would result in the rigour state characteristic of rigor mortis.
12. Once another ATP binds to myosin, the myosin head will again detach from actin and crossbridge cycle will restart.
13. As long as there are sufficient amounts of ATP and Ca2+ in the cytoplasm. crossbridge cycling can continue indefinitely.
14. Termination of crossbridge cycling occurs when Ca2+ ions are actively pumped back into the Sarcoplasmic Reticulum.
15. When Calcium is no longer present on the thin filament, Tropomyosin chances conformation back to its previous state, blocking the binding sites again.
16. Myosin ceases binding to the thin filament, and the muscle relaxes.
17. Ca2+ ions leave Troponin in order to maintain the Ca2+ ion concentration in the Sarcoplasm.
18. Active pumping of Ca2+ ions into the SR creates a deficiency in the fluid around the myofibrils.
19. This causes the removal of Ca2+ ions from the Troponin.
20. Thus, the Tropomyosin-Troponin complex again covers the binding sites on the Actin filaments and muscle contraction ceases.
The strength of skeletal muscle contractions can be broadly separated into:
— Twitch = This describes a single contraction and relaxation cycle produced by an action potential within the muscle fibre itself. The time between a stimulus to the motor nerve and the subsequent contraction of the innervated muscle is called the latent period. This period lasts about 10ms and is usually caused by the time taken for nerve action potential to propagate, the time for chemical transmission at the neuromuscular junction, then the subsequent steps in excitation-contraction coupling.
— Summation = This occurs when another muscle produces another action potential before the complete relaxation of a muscle twitch, thence the next twitch will simply sum onto the previous twitch. There are 2 types of summation: frequency summation and multiple fibre summation.
- Frequency summation occurs when force exerted by the skeletal muscle is controlled by varying the frequency at which action potentials are transferred to muscle fibres. Action potentials usually don’t arrive at muscles synchronously. However, during contraction, a fraction of the muscle fibres may fire at any given time. For instance, when a human n is exerting a muscle as hard as he/she is consciously able, approximately 1/3 of the fibres in that muscle will be firing simultaneously, though this ratio can be affected by various physiological and psychological factors such as Golgi Tendon Organs and Renshaw Cells. This 'low' level of contraction protects the tendon from avulsion, because the force generated by a 95% contraction of all fibres is sufficient to damage the body.
- Multiple Fibre summation occurs when the CNS transmits a weak nerve signal to contract a muscle, only the smaller motor units are activated first because they are more excitable than the larger motor units. As the strength of the signal increases, more motor units are excited in addition to the larger ones, with the largest motor units possessing as much as 50 times the contractile strength as the smaller ones. As more and larger motor units are activated, force of muscle contraction becomes progressively stronger. This concept is known as the size principle, which refers to the gradation of muscle force occurring in small steps during weak contraction. This effect progressively gets larger when greater amounts of force are required.
— Tetanus = This occurs when frequency of muscle action potentials increases such that the muscle contraction reaches its peak force and plateaus at this level.
Known as Hill’s Muscle Model, the length-tension relationship associates the strength of an isometric contraction with the length of the muscle at which the contraction occurs. Muscles operate with greatest active tension when close to an ideal length, which is often their resting length. When the muscle is stretched or shortened beyond this ideal length, the maximum active tension generated decreases. This decrease is minimal for small deviations, but the tension decreases rapidly as the deviation from the ideal length increases. In reality, as the muscle is stretched beyond a given length, there is an entirely passive tension, which opposes lengthening. This is due the presence of elastic proteins within a muscle cell (such as Titin) and extracellular matrix. Combined together, there is a strong resistance to lengthening an active muscle far beyond the peak of active tension.
The force-velocity relationship associates the speed at which a muscle changes its length with the the amount of force that it generates. Force declines in a hyperbolic fashion relative to the isometric force as the shortening velocity increases, eventually reaching zero at a certain maximum velocity. In contrast to when the muscle is stretched, force increases above an isometric maximum, until finally reaching an absolute maximum. This intrinsic property of active muscle tissue plays a role in the active damping of joints, which are actuated by simultaneously-active opposing muscles. In such cases, this force-velocity profile enhances the force produced by the lengthening muscle at the expense of the shortening muscle. Whichever muscle returns the joint to equilibrium effectively is favoured, because it increases the damping of such joint. Moreover, the strength of the damping increases with muscle force. Thus, the motor system can actively control joint damping via the co-contraction of opposing muscle groups.
(B) Smooth Muscle
https://en.wikipedia.org/wiki/Smooth_muscle
This muscle type is an involuntary non-striated muscle. It is divided into 2 subgroups: Single-Unit (Unitary) and Multiunit smooth muscle. Within single-unit smooth muscle, the whole sheet contracts as a syncytium. Smooth muscle can be found in the walls of hollow organs, including the stomach, intestines, urinary, bladder and uterus, and in the walls of passageways, such as arteries and veins of the circulatory system, and the tracts of the respiratory, urinary, and reproductive systems. Smooth muscle cells are also present in the eyes, where it can change the size of the iris and alter the shape of the lens. Smooth muscle cells are also found in the skin, where it erects the hairs in response to cold temperature or fear. Most smooth muscle cells are unitary, meaning either the whole muscle contracts or the whole muscle relaxes. They line blood vessels (except large elastic arteries), the urinary tract and the digestive tract. Multi-unit smooth muscle is found in the trachea, large elastic arteries and the iris of the eye. Smooth muscle cells known as myocytes, have a fusiform shape which allows them to tense and relax like striated muscle. However, smooth muscle tissue tends to demonstrate greater elasticity and function within larger length-tension curve than striated muscle. This ability to stretch and still maintain contractility is important for organs to function for long periods like the intestines and urinary bladder.
Smooth muscle is primarily made of Myosin Class II:
— Myosin II contains 2 Heavy Chains which constitute the head and tail domains. Each of these heavy chains contains the N-terminal head domain, while the C-terminal tails take on a coiled-coil morphology. This holds the 2 heavy chains together like 2 snakes wrapped around each other, such as in a caduceus. In smooth muscle, there is a single gene called MYH11 that codes for the heavy chains myosin II, but there are splice variants of this gene that result in four distinct isoforms. Smooth muscle may also contain MHC that is not involved in contraction, which can arise from multiple genes.
— Myosin II also contains 4 Light Chains, including 2 per head, weighing 20 (MLC20) and 17 (MLC17) kDa. These bind the heavy chains in the "neck" region between the head and tail.
- MLC20 is also known as the “Regulatory Light Chain” and actively participates in muscle participation. 2 MLC20 isoforms are found in smooth muscle, and they are encoded by different genes, but only one isoform participates in contraction.
- MLC17 is also known as the “Essential Light Chain”. Its exact function isn’t well understood, but it's believed that it provides structural stability of the myosin head along with MLC20. As a result of alternative splicing at the MLC17 gene, 2 variants of MLC17 (MLC17a/b) exist.
There are up to 100s different combinations of Heavy and Light chains that make up the Myosin structures, but it is unlikely that more than a few such combinations are actually used or permitted within a specific smooth muscle bed. For example, in the uterus, a shift in Myosin expression has been hypothesised to anticipate changes in the directions of uterine contractions observed during the menstrual cycle.
Thin filaments are predominantly composed of α- and γ-Actin, which form part of the contractile machinery, but in smooth muscle, it’s predominantly α-Actin. Other isoforms of Actin like β-actin don’t participate in contraction, but they undergo polymerisation below the plasma membrane in the presence of a contractile stimulant and may thereby assist in mechanical tension. Ratio of Actin to Myosin is between 2:1 and 10:1 in smooth muscle. Conversely, according to the mass ratio, Myosin is the dominant protein in striated skeletal muscle with the Actin to Myosin ratio falling in the 1:2 to 1:3 range. A typical value for healthy young adults is 1:2.2.
Unlike skeletal muscle, smooth muscle doesn’t contain Troponin, instead it contains Calmodulin (which plays a regulatory role in smooth muscle), Caldesmon and Calponin.
— Tropomyosin is present in smooth muscle, spanning 7 Actin monomers and is laid out end to end over the entire length of the thin filaments. However, its true function in smooth muscle is unknown.
— Calponin may exist in equal number as Actin, and could play a role in load-bearing.
— Caldesmon is proposed to be involved in tethering actin, myosin and tropomyosin, thereby enhancing the ability of smooth muscle to maintain tension.
— Furthermore, all 3 of these proteins may play an important role in inhibiting the ATPase activity of the myosin complex that otherwise provides energy to fuel muscle contraction.
Actin filaments of contractile units are attached to dense bodies, which are rich in α-actinin and attach intermediate filaments consisting largely of Vimentin and Desmin. This suggests they serve as anchors from which the thin filaments can exert force. Dense bodies also are associated with β-actin, which is found in the cytoskeleton. This suggests that dense bodies may coordinate tensions from both the contractile machinery and the cytoskeleton.
The intermediate filaments are connected to other intermediate filaments via dense bodies, which eventually are attached to Adherens Junctions in the Sarcolemma of the Myocyte. Adherens Junctions consist of large number of proteins including α-Actinin, Vinculin and cytoskeletal Actin, and they are scattered around dense bands, which are circumferencing the smooth muscle cell in a rib-like pattern. The dense band (or dense plaques) areas alternate with regions of membrane containing numerous cavaolae, which I’ll discuss later on. When Actin-Myosin complexes contract, force is transduced to the Sarcolemma through intermediate filaments attaching to such dense bands. During smooth muscle contraction, in order to optimise force development, space reorganisation occurs when Vimentin becomes phosphorylated at Serine-56 by a p21 activated Kinase, resulting in Vimentin polymers being disassembled. Also, the number of Myosin filaments is dynamic between the relaxed and contracted state in some tissues as the Actin to Myosin ratio changes, and the length and number of Myosin filaments change. It’s known myocytes contract in a spiral corkscrew fashion and contractile proteins organise into zones of actin and myosin along the axis of the cell. If smooth muscle-containing tissue requires consistent stretching, then it requires elasticity. Thus, myocytes secrete a complex extracellular matrix containing Collagen (predominantly Types I and III), Elastin, Glycoproteins and Proteoglycans. Smooth muscle also contains specific elastin and collagen receptors to interact with these proteins of the extracellular matrix, which help contribute to the viscoelasticity of these tissues. e.g. Great arteries are viscolelastic vessels that act like a Windvessel. It propagates ventricular contraction and smooths out the pulsatile flow, and the smooth muscle within the Tunica Media contributes to this attribute.
The Sarcolemma also contains caveolae, which are microdomains of lipid rafts specialised to cell signalling events and ion channels. These invaginations in the sarcoplasma contain:
— A host of receptors including Prostacyclin, Endothelin, Serotonin, Muscarinic Receptors, Adrenergic Receptors.
— Second Messenger generators including Adenylate Cyclase, Phospholipase C
— G-Proteins including RhoA and G-α (G-alpha)
— Kinases including Rho-Kinase-ROCK, Protein Kinase C, Protein Kinase A
— Ion channels including L-Type Calcium channels, ATP-sensitive Potassium channels, Calcium-sensitive Potassium channels
The caveolae are often close to SR or Mitochondria, and have been theorised to play a role in organising signalling molecules in the membrane.
Smooth muscle undergo excitation-contraction coupling by external stimuli, causing contraction. Each step is discussed below:
a) Inducing stimuli and factors
Smooth muscle may contract spontaneously (via ionic channel dynamics). Nevertheless, in the gut, special pacemakers cells called Interstitial Cells of Cajal produce rhythmic contractions. These processes, as well as relaxation are induced by a number of physiochemical agents like hormones, drugs and neurotransmitters, particularly from the autonomic nervous system. Smooth muscle in various regions of the vascular tree, the airway and lungs, kidneys and vagina is different in their expression of ionic channels, hormone receptors, cell-signalling pathways, and other proteins that determine function.
e.g. Blood vessels in skin, gastrointestinal system, kidney and brain respond to Noradrenaline and Adrenaline secreted by the Sympathetic Nervous System or the Adrenal Medulla. This causes them to vasoconstrict, which is mediated through α-1 Adrenergic Receptors. However, blood vessels within skeletal muscle and cardiac muscle respond to these catecholamines, which causes them to vasodilate because smooth muscle expresses β-Adrenergic Receptors. This contrast in the distribution of the various adrenergic receptors explains the difference in blood vessel reactions from different areas in response to the same molecule i.e. Noradrenaline / Adrenaline as well as varying amounts of these catecholamines being released and sensitivities of various receptors to concentrations.
— Arterial smooth muscle vasodilates in the presence of Carbon Dioxide, and vasoconstricts in the presence of Oxygen.
— Pulmonary blood vessels within the lung are unique as they vasodilate to high Oxygen tension and vasoconstrict when it falls.
— Smooth muscle lining the airways of the lung like Bronchioles vasodilate to high Carbon Dioxide levels and vasoconstrict to low Carbon Dioxide levels.
These responses to Carbon dioxide and Oxygen by pulmonary blood vessels and bronchiole airway smooth muscle aid in matching perfusion and ventilation within the lungs. Further different smooth muscle tissues display ranges of SR from abundant to lacking so excitation-contraction coupling varies with its dependence on intracellular or extracellular Calcium.
Recent research has uncovered Sphingosine-1-Phosphate (S1P) signalling playing an important role as a regulator of vascular smooth muscle contraction. When transmural pressure increases, Sphingosine Kinase 1 phosphorylates Sphingosine to S1P, which binds to the S1P2 receptor in plasma membrane of cells. This transiently increases intracellular Calcium levels, and subsequently activates Rac and Rhoa signalling pathways. Collectively, these serve to increase MLCK activity and decrease MLCP activity, and promote smooth muscle contraction. This would allow arterioles to increase its arterial resistance in response to increased blood pressure and thus maintain constant blood flow. The Rhoa and Rac portion of the signalling pathway provides a Calcium-independent way to regulate resistance artery tone.
b) Spread of impulse
Myocytes fasten to one another by Adherens Junctions in order to maintain organ dimensions against force. This means, cells are mechanically to one another such that contraction of 1 cell invokes some degree of contraction in an adjoining cell. Gap Junctions couple adjacent cells chemically and electrically in order to facilitate the spread of chemicals like Calcium or action potentials between myocytes. In unitary smooth muscle, there are numerous gap junctions situated between the myocytes, therefore these tissues are often organised into sheets or bundles in order to contract in bulk.
c) Contraction
Like skeletal muscle, the sliding of Myosin and Actin filaments over each other causes smooth muscle contraction. It receives its energy from ATP hydrolysis. Myosin functions as an ATPase, which utilises ATP to produce a molecular conformational change in part of the Myosin to produce movement. Movement occurs when the globular heads protruding from myosin filaments attach and interact with actin filaments to form crossbridges. i. The Myosin heads tilt and drag along the actin filament about 10 - 12 nm.
ii. The heads then release the Actin filament and then changes angle to relocate to another site on the Actin filament a further 10 - 12 nm.
iii. They can then re-bind to the actin molecule and drag it along further.
Like all muscles, this process is called crossbridge cycling. But unlike cardiac and skeletal muscle, smooth muscle does not contain the Calcium-binding protein Troponin. Instead contraction is initiated by a Calcium-regulated phosphorylation of Myosin, rather than a Calcium-activated Troponin system. Contraction of of myosin and actin complexes would increase tension along the entire chains of tensile structures, which ultimately contracts the entire smooth muscle tissue.
Smooth muscle may contract phasically with rapid contraction and relaxation or tonically with slow and sustained contraction. e.g. Smooth muscle in reproductive, digestive, respiratory, and urinary tracts, skin, eye, and vasculature contract tonically. This would help maintain force for prolonged time with little energy expenditure. Differences in the myosin heavy and light chains correlate with these differences in contractile patterns and kinetics of contraction between tonic and phasic smooth muscle.
i. Activation of Myosin Heads
1. When the light chains of the Myosin heads are phosphorylated by Myosin Light-Chain Kinase (MLCK, MLC20 Kinase).
2. This means crossbridge cycling can occur, hence contraction can begin.
3. Stimulation of the muscle to contract will allow MLCK to function, which would help control contraction.
4. This will increase the intracellular concentration of Calcium ions.
5. These Calcium ions bind to Calmodulin, and form a calcium-calmodulin complex.
6. This complex then binds to MLCK, which activates it.
7. This allows the chain of reactions to occur.
8. Activation involves phosphorylation of Myosin Light-Chain Kinase (MLCK, MLC20 Kinase) on Ser19 (Serine on position 19), which becomes active, undergo a conformational change that increases the angle in the neck domain of the Myosin Heavy Chain.
9. This corresponds to the part of the cross-bridge cycle where the Myosin head is unattached to the Actin filament and relocates to another site on it.
10. After attachment of the Myosin head to the Actin filament, this Ser19 phosphorylation activates the ATPase activity of the Myosin head region to provide the energy to fuel the subsequent contraction.
11. Phosphorylation of a Threonine on position 18 (Thr18) on MLC20 is also possible and may further increase the ATPase activity of the Myosin complex.
ii. Sustained Maintenance
1) Phosphorylation of the MLC20 Myosin light chains correlates with the shortening velocity of smooth muscle.
2) During this period, a rapid burst of energy expenditure occurs in correlation to Oxygen consumption.
3) Within a few minutes of this initial burst, Calcium levels markedly decrease, MLC20 Myosin light chains phosphorylation decreases, and energy expenditure decreases and the muscle relaxes.
Nevertheless, smooth muscle possesses the ability of sustained maintenance of force in this situation too. This sustained phase has been attributed to certain myosin crossbridges, known as “latch-bridges”. Latch-bridges cycle slower than crossbridges, which notably slows progression to the cycle stage whereby dephosphorylated Myosin detaches from the Actin, thereby maintaining the force at low energy costs. This phenomenon is important for tonically active smooth muscle.
If you prepared isolated samples of vascular and visceral smooth muscle in high Potassium balanced saline, they would depolarise generating contractile force. Furthermore, if you prepared the same muscle samples in normal saline filled with an agonist such as Endothelin or Serotonin, it would generate more contractile force. This increase in force being generated is described as “Calcium sensitisation”. This phenomenon involves the Myosin Light Chain Phosphatase being inhibited to increase the gain or sensitivity of Myosin Light Chain Kinase to Calcium. Scientists have proposed a number of cell signalling pathways that may be involved in regulating decreases in Myosin Light Chain Phosphatase. These pathways include a RhoA-Rock kinase pathway, a Protein kinase C-Protein kinase C potentiation inhibitor protein 17 (CPI-17) pathway, Telokin, and a Zip kinase pathway. Further Rock kinase and Zip kinase have been implicated to directly phosphorylate the 20kd Myosin light chains. Other cell signalling pathways and Protein Kinases like Protein Kinase C, Rho Kinase, Zip Kinase and Focal Adhesion Kinases have been proposed to play a role in force maintenance, as well as Actin polymerisation dynamics. e.g. Phosphorylation of specific Tyrosine residues on the Focal Adhesion Adapter Protein-Paxillin by specific Tyrosine kinases has been demonstrated to be essential to force development and maintenance. Furthermore, cyclic nucleotides can relax arterial smooth muscle without reductions in cross-bridge phosphorylation. This process is termed “force suppression”, which is mediated by the phosphorylation of the small heat shock protein, hsp20, and may prevent phosphorylated Myosin heads from interacting with Actin.
d) Relaxation
Myosin Light-Chain Phosphatase antagonises the phosphorylation of the light chains by MLCK by dephosphorylating the MLC20 Myosin Light Chains and thereby inhibits smooth muscle contraction. Generally, smooth muscle relaxation occurs when cell signalling pathways increase Myosin Phosphatase activity, decrease intracellular Calcium levels, hyperpolarise smooth muscle and/or regulate Actin and Myosin muscle which is mediated by:
— Endothelium-derived relaxing factor-Nitric Oxide
— Endothelial-derived Hyperpolarising Factor (either an endogenous cannabinoid, Cytochrome P450 metabolite, or Hydrogen Peroxide)
— Prostacyclin (PGI2)
1) Nitric Oxide and PGI2 stimulate soluble Guanylate Cyclase and membrane bound Adenylate Cyclase, respectively.
2) These cyclases then produce cyclic nucleotides (i.e. cGMP and cAMP).
3) Cyclic nucleotides then activate Protein Kinase G and Protein Kinase A and phosphorylate a number of proteins.
4) The phosphorylation events lead to a decrease in intracellular Calcium levels.
5) This would inhibit L type Calcium channels, inhibit IP3 Receptor Channels, stimulate Sarcoplasmic Reticulum Calcium pump ATPase, decrease 20kd Myosin light chain phosphorylation by altering Calcium sensitisation and increasing Myosin Light Chain Phosphatase activity.
6) This stimulates Calcium-sensitive Potassium channels which hyperpolarise the cell, and phosphorylate Serine 16 on the small heat shock protein (hsp20) by Protein Kinases A and G.
7) Phosphorylation of hsp20 alters Actin and focal adhesion dynamics and Actin-Myosin interaction, and possibly bind to 14-3-3 protein. The impact of phosphorylated hsp20 remains unclear, but there are theories suggesting it may alter the affinity of phosphorylated Myosin with Actin and inhibit contractility by interfering with the crossbridge formation.
8) The Endothelium-derived Hyperpolarising Factor stimulates Calcium-sensitive Potassium channels and/or ATP-sensitive Potassium channels.
9) This stimulates Potassium efflux which hyperpolarises the cell and produces smooth muscle relaxation.
Although the structure and function is identical in smooth muscle cells in different organs, their specific effects or end-functions differ.
For example, the contractile function of vascular smooth muscle regulates the lumenal diameter of the small arteries-arterioles called “resistance vessels”. This contributes significantly to setting the level of blood pressure and blood flow to vascular beds. In reality, smooth muscle contracts slowly in order to maintain the contraction (tonically) for prolonged periods in blood vessels, bronchioles, and certain sphincters. Stimulating arteriole smooth muscle decreases the lumenal diameter to a third of resting diameter, which drastically alters blood flow and resistance. Stimulation of aortic smooth muscle doesn't significantly alter the lumenal diameter but serves to increase the viscoelasticity of the vascular wall.
In the gastrointestinal tract, smooth muscle contracts in a rhythmic peristaltic fashion, that is, rhythmically forcing food chunks through the digestive tract as the result of phasic contraction.
Within the afferent arteriole of the juxtaglomerular apparatus, smooth muscle there demonstrates a non-contractile function. It secretes Renin in response to osmotic and pressure changes, which in turn, activates the Renin-Angiotensin system to regulate blood pressure. Moreover, it secretes ATP in tubuloglomerular regulation of glomerular filtration rate.
I’ll delve into digestion in another post.
(C) Cardiac Muscle
https://en.wikipedia.org/wiki/Cardiac_muscle
Also known as heart muscle or myocardium, cardiac muscle is an involuntary, striated muscle that constitutes the main tissue of the walls of the heart. The heart wall is made of 3 layers: An outer epicardium (visceral pericardium), a middle layer of myocardium and an inner endocardium. The inner endocardium lines the cardiac chambers, covers the cardiac valves, and adheres to the endocardium lining the blood vessels that connect to the heart. The outer epicardium is a sack that surrounds, protects, and lubricates the heart. Within the myocardium there are several sheets of cardiac muscle cells or Cardiomyocytes, which wrap around the left ventricle closest to the endocardium and are oriented perpendicularly to those closest to the epicardium. These sheets contract in a coordinated manner, which allows the ventricle to squeeze in several directions simultaneously. Those direction include longitudinal (shortening from apex to base), radial (narrowing from side to side), and twisting (like wringing out a damp cloth) to squeeze out evert drop of blood with each heartbeat. Cardiac muscle contraction requires high energy expenditure, hence it relies on the constant flow of blood to provide Oxygen and nutrients. Blood is delivered to the myocardium by the coronary arteries, which originate from the Aortic Root and then lie on the outer or epicardial surface of the heart. Blood is then drained away by the Coronary Veins into the Right Atrium.
https://en.wikipedia.org/wiki/Cardiac_muscle_cell
Cardiac muscle are made out of cells called cardiomyocytes, which contract to allow the heart to pump blood. Each cardiomyocyte needs to coordinate its contraction with neighbouring cells in order to pump blood from the heart efficiently and rhythmically. If coordination is lacking, the heart would fail to pump at all. This causes abnormal heart rhythms such as ventricular fibrillation. Each cell contains myofibrils, which are specialised protein fibres that slide past each other. These are organised into sarcomeres to form the fundamental contractile units of muscle cells. This gives cardiomyocytes a striped or striated appearance, like in skeletal muscle. These striations are caused by lighter I-bands composed mainly of Actin, and darker A-bands composed mainly of Myosin. A majority of cardiomyocytes contain from as little as 1 to as many as 4 nuclei. They contain many mitochondria in order provide the energy i.e. ATP required for cardiomyocytes to resist fatigue.
There are 2 types of cardiac muscle cells within the heart:
— Cardiomyocytes form the structure of the atria and the ventricles of the heart. Atria (plural for atrium) are the chambers in which blood enters the heart, while ventricles are the chambers where blood is collected and pumped out of the heart. Cardiomyocytes must be able to shorten and lengthen their fibres and the fibres must be flexible enough to stretch. These functions are critical in maintaining the continuous, rhythmic beating of the heart.
— Cardiac Pacemaker Cells carry the electrical impulses that kickstart the heartbeat, which become distributed throughout the heart. They play an important role in spontaneously generating and transmitting electrical impulses, as well as receiving and responding to electrical impulses from the brain. Furthermore, they help transfer electrical impulses rapidly from cell to cell throughout the heart.
All cardiac muscle cells are connected by cellular bridges called intercalated discs, which form important junctions between the cells. These are porous junctions that allow Sodium, Potassium and Calcium ions to easily diffuse from cell to cell, which helps depolarise and repolarise the myocardium swiftly. Because of these junctions and bridges, the heart muscle is able to perform as a single coordinated unit.
Cardiac action potentials consists of 2 cycles: systole (rest phase) and diastole (active phase). During systole, the resting potential separates the ions such as Sodium, Potassium and Calcium. This allows myocardial cells to automatically or spontaneously depolarise, which is a direct result of a membrane which allows Sodium ions to slowly enter the cell until the threshold is reached for depolarisation. Then Calcium ions follow suit and prolong the depolarisation event. Once Calcium influx halts, Potassium ion efflux occurs slowly to cause repolarisation. The sluggish repolarisation of the cardiomyocyte membrane accounts for the long refractory period.
https://en.wikipedia.org/wiki/T-tubule
Cardiomyocytes also contain T-Tubules, which are pouches of membrane running from the surface to the cell's interior that help improve the efficiency of contraction. T-Tubules are continuous with the cell membrane, composed of the same Phospholipid bilayer, and are open at the cell surface to the extracellular fluid surrounding the cell. Compared to skeletal muscle, there aren’t as many T-Tubules but they are larger and wider in size. They adhere at the centre of the cell, then run into and along the cell as a transverse-axial network. Once inside, they lie adjacent to the Sarcoplasmic Reticulum, which is the cell’s internal Calcium store. Here, a single T-Tubule pairs with part of the sarcoplasmic reticulum called a terminal cisterna to form a combination known as a diad. T-Tubules rapidly transmit action potentials from the cell surface to the cell's core, and help regulate Calcium concentration within the cell in a process known as “excitation-contraction coupling”.
The shape of the T-tubule system is produced and maintained by a variety of proteins:
— Amphyphysin-2 is encoded by the gene BIN-1. This protein is responsible for forming the structure of the T-tubule and ensuring that the appropriate proteins (i.e. L-Type Calcium channels) are located within the T-tubule membrane.
— Junctophilin-2, which is encoded by the gene JPH2, is responsible for creating the vital junction between the T-tubule membrane and the Sarcoplasmic Reticulum for excitation-contraction coupling.
— Titin capping protein or Telethonin is encoded by the gene TCAP and helps with T-tubule development and is potentially responsible for the increasing number of T-tubules seen as muscles grow.
https://en.wikipedia.org/wiki/Intercalated_disc
When you view cardiomyocytes under a microscope, you will notice they are joined together at their ends by intercalated discs to form long fibres. These discs help create a network of cardiomyocytes called the cardiac syncytium, which can rapidly transmit electrical impulses throughout the network. This enables the syncytium to contract in a coordinated fashion. The cardiac connection fibres also connect to an atrial syncytium and a ventricular syncytium. Electrical resistance through intercalated discs is quite minimal, thus allowing free diffusion of ions along cardiac muscle fibres axes. This would allow action potentials to travel from one cardiac muscle cell to the next with little resistance. Each syncytium obeys the all-or-none law. Intercalated discs are complex adhering structures that connect the single cardiomyocytes to an electrochemical syncytium and transmit force during muscle contraction. Intercalated discs consist of 3 different types of cell-cell junctions: Adherens Junctions (anchors Actin filaments), Desmosomes (anchors Intermediate filaments) and Gap Junctions. These intercalated discs provides a passage for ions between cells, which allows action potentials to spread between cardiomyocytes, hence depolarise the cardiac muscle. Recent molecular biological and comprehensive studies unequivocally discovered a mixed-type Adherens Junctions named area composita that appear an amalgamated form of typical desmosomal and fascia adhaerens proteins. These findings would help understand the mechanisms of inherited cardiomyopathies.
https://en.wikipedia.org/wiki/Fibroblast
Situated within cardiac muscle are vital supporting cells called fibroblasts. Although they don’t participate in cardiac muscle contraction, they are responsible for creating and maintaining the extracellular matrix which forms the mortar in which Cardiomyocyte bricks are embedded. They play a crucial role in responding to injury, such as a myocardial infarction. Following injury, Fibroblasts become activated and differentiate into Myofibroblasts, which exhibit behaviour reminiscent of a fibroblast and a smooth muscle cell i.e. Generating extracellular matrix and contracting to produce force. This allows myofibroblasts to repair an injury by creating Collagen while gently contracting to pull the edges of the injured area together. Fibroblasts are smaller but more numerous than Cardiomyocytes, and several of them are attached to a Cardiomyocyte at once. When attached, they can influence the electrical currents passing across the muscle cell's surface membrane, a process known as electrical coupling. Other potential functions of fibroblasts include electrical insulation of the cardiac conduction system, and the ability to transform into other cell types including cardiomyocytes and Adipocytes.
Surrounding the Cardiomyocyte and Fibroblasts is the extracellular matrix, which is composed of proteins such as Collagen and Elastin, and Polysaccharides known as Glycosaminoglycans. Together, these substances provide support and strength to the muscle cells, creating elasticity in cardiac muscle, and keeping the muscle cells hydrated by binding water molecules. Matrix immediately contacting with cardiomyocytes is often referred as the “basement membrane”, mainly composed of Type IV Collagen and Laminin. Cardiomyocytes are linked to this basement membrane via specialised Glycoproteins called Integrins.
The physiology of cardiac muscle including the process of excitation-contraction coupling is similar to that of skeletal muscle. Both muscle types contract, requires an action potential to contract which increases Calcium concentration within the cytosol. However, there are differences in regards to the mechanisms by which calcium concentrations within the cytosol rise. Unlike skeletal muscle, action potentials in cardiac muscle comprises an inward flow of both Sodium and Calcium ions. However, the flow of Sodium ions is rapid and temporary, while the flow of Calcium ions is sustained and would plateau over the long term. The comparatively small flow of Calcium ions through L-Type Calcium channels triggers a substantial release of Calcium ions from the Sarcoplasmic Reticulum in a phenomenon known as “Calcium-induced Calcium release”.
In cardiac muscle contraction, long protein myofilaments oriented along the length of the slide over each other. There are 2 types of myofilaments: “thick filaments” are composed of Myosin, whilst “thin filaments” are composed of Actin, Troponin and Tropomyosin. As the thick and thin filaments slide past each other, the cardiac muscle cell shortens and expands. Therefore, like skeletal muscle, cardiac muscle undergoes the identical crossbridge cycling process.
https://en.wikipedia.org/wiki/Bioenergetic_systems
Muscular activity accounts for much of the human body’s energy consumption. The metabolic processes responsible for the flow of energy in living organisms are called bioenergetic systems. The cellular respiration process converts food energy into ATP (a form of energy), but it largely depends on the availability of Oxygen. During exercise, the supply and demand of oxygen available to muscle cells is influenced by duration and intensity and by the individual's cardiorespiratory fitness level. There are 3 exercise energy systems the body selectively recruits, depending on the amount of oxygen available, as part of the cellular respiration process to generate the ATP for the muscles.
When ATP is decomposed, energy is released. But more energy is required to rebuild or re-synthesise it. The building blocks of ATP synthesis are the by-products of its breakdown: Adenosine Diphosphate (ADP) and inorganic Phosphate (Pi). The energy for ATP re-synthesis comes from 3 different series of chemical reactions that take place within the body. 2 of the 3 rely on the food you eat, whereas the other relies on a chemical called Phosphocreatine. Energy released from any of the 3 series of reactions then couples with the energy needs of the reaction tasked to re-synthesise ATP. Each reaction is functionally linked together in such a way that the energy released by the one is always used by the other.
(1) ATP-CP: Phosphagen System
Every cycle of this system lasts about 10 seconds. It doesn’t require Oxygen nor produce Lactic Acid if Oxygen is unavailable and is thus said to be alactic anaerobic. This system is often recruited for brief, powerful movements like a golf swing, a 100m sprint or powerlifting.
Like ATP, Creatine Phosphate (CP) is stored in muscle cells. A large amount of energy is released when it’s decomposed, which becomes to to the energy requirement necessary for ATP re-synthesis. The total muscular stores of both ATP and CP are small, which limits the amount of energy obtainable through this system. Therefore, the Phosphogen stored in the working muscles is typically exhausted within seconds of vigorous activity. However, the usefulness of this system lies in the rapid availability of energy rather than quantity.
(2) Anaerobic System:
Also known as the glycolytic system, it predominates in supplying energy via anaerobic glycolysis for exercises lasting less than 2 minutes such as the 400m sprint. Anaerobic refers to the series of chemical reactions that don’t require Oxygen. “Glycolysis” refers to the breakdown of sugar (Glucose), which supplies the necessary energy from which ATP is manufactured. When Glucose metabolises anaerobically, it partially breaks down to form Lactic Acid, 1 of its by-products. This process generates enough energy to couple with the energy requirements to re-synthesise ATP. When protons (H+ ions) accumulate in the muscles, this decreases blood pH causing temporary muscle fatigue. Because only a few moles of ATP can be re-synthesised anaerobically, this system cannot be relied on for extended periods of time.
(3) Aerobic System:
This energy system has a longer duration. After 5 mins of exercise, the Oxygen system is dominant. In a 1 km run, the aerobic system provides approximately 50% of the energy, and in a marathon run it provides 98% or more. Aerobic refers to the presence of Oxygen. There are several stages:
i. Glycolysis = This process breaks down Glucose to produce 2 ATP molecules, 2 reduced molecules of Nicotinamide Adenine Dinucleotide (NADH) and 2 Pyruvate molecules that move on to the next stage. It takes place in the cytoplasm of normal body cells or the sarcoplasm of muscle cells.
ii. Krebs Cycle = This process breaks down Pyruvate through a series of steps to produce 1 ATP, 1 Carbon Dioxide molecule, 3 reduced NAD molecules, 1 reduced NADH (FAD) molecule. NAD and FAD are electron carriers, and if they are said to be reduced, this means that they have had one H+ ion added to them. The metabolites are for each turn of the Krebs cycle, which turns twice for each molecule of Glucose that passes through the aerobic system as 2 Pyruvate molecules enter the Krebs cycle. In order for the pyruvate molecules to enter the Krebs cycle they must be converted to Acetyl Coenzyme A. During this link reaction, when each molecule of Pyruvate converted to Acetyl Coenzyme A, 1 NAD is also reduced. This stage of the aerobic system takes place in the matrix of the cells’ mitochondria.
iii. Oxidative Phosphorylation = The process produces the largest yield of ATP out of all the stages of the aerobic system, about a total of 34 ATP molecules. Oxidative Phosphorylation refers to Oxygen acting as the final acceptor of the electrons and protons, leaving this stage of aerobic respiration (hence oxidative) and ADP phosphorylates (i.e. an extra Phosphate gets added) to form ATP (hence phosphorylation). This stage occurs on the cristae, or infoldings on the membrane of the mitochondria. The NADH+ from the Glycolysis and Krebs cycle stages, and the FADH+ only from the Krebs cycle stage produce electron carriers at decreasing energy levels, in which energy is released to reform ATP. Each NADH+ and FADH+ molecule that travels along the Electron Transport Chain provides adequate energy for 3 ATP and 2 ATP respectively. This adds up to 10 NADH+ and 2 FADH+ molecules, which allows the rejuvenation of 30 ATP and 4 ATP molecules respectively. This adds up to 34 from oxidative phosphorylation, plus the 4 from the previous 2 stages meaning a total of 38 ATP being produced during the aerobic system. The NADH+ and FADH+ get oxidised to allow the NAD and FAD to return to be used in the aerobic system again. Furthermore, electrons and protons are accepted by Oxygen to produce another by-product called water.
I’ll delve into the steps of Glycolysis, Krebs cycle, Oxidative Phosphorylation and Electron Chain Transport in greater detail in another post.
Defined as the ratio of mechanical work to the metabolic cost, as calculated from Oxygen consumption, the efficiency of human muscle has been measured at 18 - 26%, which isn’t that efficient. This is because the efficiency of generating ATP from food energy is about 40%. Energy losses are mainly due to mechanical work inside the muscle, and mechanical losses inside the body, depending on the type of exercise and the type of muscle fibres being used (fast-twitch or slow-twitch). At 20% efficiency, 1 Watt of mechanical power is equivalent to 4.3 kcal per hour. This conversion is what manufacturers of rowing equipment calibrate its rowing ergometer to count burned calories as equal to 4 times the actual mechanical work, plus 300 kcal per hour, which adds up to 250 W of mechanical output. The mechanical energy output of a cyclic contraction depends upon many factors, including activation timing, muscle strain trajectory, and rates of force rise & decay, which can be synthesised experimentally using work loop analysis.
How strong is muscle?
Muscle strength relies on 3 overlapping factors:
— Physiological Strength = Includes muscle size, cross sectional area, available cross-bridging, responses to training
— Neurological Strength = Strength of nerve signal instructing the muscle to contract
— Mechanical Strength = Muscle's force angle on the lever, moment arm length, joint capabilities
Vertebrate muscle typically produce about 25 - 33 N (5.6 - 7.4 lbf) of force per cm2 of muscle cross-sectional area when isometric and at optimal length. Some invertebrate muscles, such as in crab claws, have much longer Sarcomeres than vertebrates, resulting in more sites for Actin and Myosin to bind and thus much greater force per cm2 at the cost of much slower speed. The force generated by a contraction can be measured:
— Non-invasively using either mechanomyography or phonomyography
— In vivo using tendon strain (if a prominent tendon is present)
— Directly using more invasive methods.
In terms of force exerted on the skeleton, the strength of any given muscle depends upon muscle length, shortening speed, cross sectional speed, pennation, Sarcomere length, Myosin isoforms, and neural activation of motor units.
What is the “strongest” human muscle?
In reality, muscles never work individually but collectively. Since 3 factors influence muscular strength, it is misleading to compare strength in individual muscles.
— In ordinary parlance, muscular "strength" usually refers to the ability to exert a force on an external object like lifting a weight. By this definition, the masseter or jaw muscle is the strongest muscle. In the 1992 Guinness Book of Records recorded the strongest bite strength ever of 4337 N (975 lbf) for 2 seconds.
— If "strength" refers to the force exerted by the muscle itself, for instance, on the place where it inserts into a bone, then the strongest muscles are those with the largest cross-sectional area. This is because the tension exerted by an individual skeletal muscle fibre doesn’t vary much, with each fibre exerting a force of about 0.3 μN. By this definition, the strongest muscle of the body is usually said to be the quadriceps femoris or the gluteus maximus.
— Because muscle strength is determined by cross-sectional area, a shorter muscle will be stronger by weight than a longer muscle of the same cross-sectional area. This would make the myometrial layer of the uterus the strongest muscle by weight in the female human body. During childbirth, the entire human uterus weighs about 1.1 kg (40 oz) and exerts 100 to 400 N (25 to 100 lbf) of downward force with each contraction.
— The external muscles of the eye are conspicuously large and strong in relation to the small size and weight of the eyeball. Eye movements particularly saccades during which the eyes are facial scanning and reading, require high speed movements, and eye muscles are exercised nightly during REM sleep.
— Reports touted the tongue as the strongest muscle in the body but it is difficult to find any definition of "strength" that would make this statement true. Note that the tongue is made up of 8 muscles, not 1.
— Other reports claim the heart is the strongest muscle because it performs the largest quantity of physical work in the course of a lifetime. It’s estimated it exerts power output of 1 - 5 W. This is much less than the maximum power output of other muscles like the quadriceps (100 W), but only for a few minutes. In reality, the heart works continuously over an entire lifetime without pause, thus it “outworks” other muscles. An output of 1W continuously for about 80 years yields a total work output of 2.5 GigaJoules.
- Why do we have muscle?
- How did it form in the first place?
- What was the first organism to develop muscle?
There are hypotheses that the evolutionary origin of muscle cells were in metazoans, but it’s met with speculation. Some scientists believed that muscle cells evolved once and thus all animals with muscles cells have a single common ancestor. Other scientists believe muscles cells evolved more than once and any morphological or structural similarities are due to convergent evolution and genes that predate the evolution of muscle and even the mesoderm.
In their 2005 study “Evolution of striated muscle: Jellyfish and the origin of triploblasty”, Schmid and Seipel argue that the origin of muscle cells is a monophyletic trait that occurred concurrently with the development of the digestive and nervous systems of all animals, which can be traced to a single metazoan ancestor in which muscle cells are present. The molecular and morphological similarities between the muscles cells in cnidaria and ctenophera, as well as bilaterians, suggest there may be one ancestor in metazoans from which muscle cells derive. Hence, Schmid and Seipel claim that the last common ancestor of bilateria, ctenophora, and cnidaria was a triploblast (an organism with 3 germ layers, and that diploplasty (an organism with 2 germ layers) evolved secondarily due to their observation of the lack of mesoderm or muscle found in most cnidarians and ctenophores. When Schmid and Seipel compared the morphology of cnidarians and ctenophores to bilaterians, they concluded that there were myoblast-like structures in the tentacles and gut of some species of cnidarians and in the tentacles of ctenophores. Since these structures are unique to muscle cells, they determined that this is a marker for striated muscles similar to those observed in bilaterians. They also remark that the muscle cells found in cnidarians and ctenophores are often contests due to the origin of these muscle cells being the ectoderm rather than the mesoderm or mesendoderm. Critics refute this claim and argue that the origin of true muscles is the endoderm portion of the mesoderm and the endoderm. However, Schmid and Seipel counter this skepticism by scrutinising the muscle cells found in ctenophores and cnidarians as not true muscle cells by considering the fact that cnidarians develop through a medusa stage and polyp stage. To support their counter-claim, they observe that in the hydrozoan medusa stage there is a layer of cells that separate from the distal side of the ectoderm to form the striated muscle cells similar to that of the mesoderm. They call this 3rd separated layer of cells “the ectocodon”. Furthermore, they argue that not all muscle cells are derived from the mesendoderm in bilaterians like the eye muscles of vertebrates and the muscles of spiralians, with such cells deriving from the ectodermal mesoderm rather than the endodermal mesoderm. Since myogenesis occurs in cnidarians thanks to molecular regulatory elements found in the specification of muscles cells in bilaterians, there is evidence for a single origin for striated muscle.
In contrast to Schmid’s and Seipel’s hypothesis, a 2012 Steinmetz et al. study “Independent evolution of striated muscle in cnidarians and bilaterians” argues that molecular markers such as the Myosin II used to determine this single origin of striated muscle actually predate the formation of muscle cells. He points out the contractile elements present in the porifera or sponges that do truly lack this striated muscle containing this protein. From their analysis of morphological and molecular markers, Steinmetz et al. presents evidence for a polyphyletic origin of striated muscle cell development that are present in bilaterians and absent in cnidarians, ctenophores, and bilaterians. They demonstrated that the traditional morphological and regulatory markers like Actin, and other MyHC elements are present in all metazoans not just the organisms that have been shown to have muscle cells. Based on this evidence, they conclusively question whether the usage of any of these structural or regulatory elements is adequate to determine whether or not the muscle cells of the cnidarians and ctenophores are similar enough to the muscle cells of the bilaterians to confirm a single lineage. Steinmetz et al. expounds on the orthologues of the MyHc genes used to hypothesise the origin of striated muscle occurred through a gene duplication event that predates the first true muscle cells. Furthermore they indicated the presence of MyHC genes in the sponges that have contractile elements but true muscle cells were lacking. Furthermore, Steinmetz et al. demonstrated the localisation of this duplicated set of genes that serve both the function of facilitating the formation of striated muscle genes and cell regulation and movement genes were already segregated into both striated and non-muscle MyHc. This event is shown through the localisation of the striated MyHc to the contractile vacuole in sponges while the non-muscle MyHc was more diffusely expressed during developmental cell shape and change. Furthermore, Steinmetz et al. discovered a similar pattern of localization in cnidarians with (except N. vectensis) this striated muscle marker present in the smooth muscle of the digestive track. Therefore, they argue that the pleisiomorphic trait of the separated orthologues of MyHc cannot be used to determine the monophylogeny of muscle, as well as the presence of a striated muscle marker in the smooth muscle of this cnidarian infers a fundamentally different mechanism of muscle cell development and structure in cnidarians. Moreover, Steinmetz et al. continue to argue for multiple origins of striated muscle in the metazoans. They discuss a key set of genes used to form the Troponin complex for muscle regulation and formation in bilaterians is missing from the cnidarians and ctenophores, and of 47 structural and regulatory proteins observed. They conclude they failed to find even on unique striated muscle cell protein that was expressed in both cnidarians and bilaterians. It seems the Z-disc evolved differently even within bilaterians, suggesting a greater diversity of proteins had developed between this clade, showing a large degree of radiation for muscle cells. Through this divergence of the Z-disc, Steimetz et al. explain the presence of 4 common protein components in all bilaterians muscle ancestors. Out of these 4 necessary Z-disc components, only Actin is an uninformative marker through its pleisiomorphic state is present in cnidarians. Following further molecular marker testing, Steinmetz et al. observed that non-bilaterians lack many regulatory and structural components necessary for bilaterians muscle formation. They failed to find any set of proteins unique to both bilaterians, cnidarians and ctenophores that aren’t present in earlier, more primitive animals like the sponges and amoebozoans. In conclusion, due to the lack of elements that bilaterians muscles are dependent on for structure and usage, nonbilaterian muscles must be of a different origin with a different set regulatory and structural proteins.
In their 2015 paper “Too many ways to make a muscle: Evolution of GRNs governing myogensis”, Andrikou and Arnone analysed the newly available data on gene regulatory networks (GRNs) in order to understand how the hierarchy of genes and morphogens and other mechanism of tissue specification diverge and are similar among early deuterostomes and protostomes. By understanding not only what genes are present in all bilaterians but also the time and place of deployment of these genes, Andrikou and Arnone undertook a deeper approach of evolution of myogenesis. According to them, understanding the function of transcriptional regulators in the context of other external and internal interactions is crucial to truly comprehending the evolution of muscle cells. Their analysis uncovered conserved orthologues of the GRNs in both invertebrate bilaterians and in cnidarians. Having this common, general regulatory circuit would have allowed for a high degree of divergence from a single well functioning network. Andrikou and Arnone also discovered that the orthologues of genes found in vertebrates had been changed through different types of structural mutations in the invertebrate deuterostomes and protostomes. They believed these structural changes in the genes allowed for a large divergence of muscle function and muscle formation in these species. Furthemore, they recognised not only any difference due to mutation in the genes found in vertebrates and invertebrates but also the integration of species specific genes that could also cause divergence from the original gene regulatory network function. These differences are theorised to be accounted by mutations in the genes found in vertebrates and invertebrates but also the integration of species specific genes that could also cause divergence from the original gene regulatory network function. This evidence suggests myogenic patterning framework may be an ancestral trait. Nevertheless, Andrikou and Arnone recommended combining the basic muscle patterning structure with the cis regulatory elements present at different times during development. In contrast with the high level of gene family apparatuses structure, they discovered that the cis regulatory elements weren’t well conserved both in time and place in the network, which could lead to a large degree of divergence in the formation of muscle cells. This analysis suggested that the myogenic GRN is an ancestral GRN with actual changes in myogenic function and structure possibly being linked to later co-opts of genes at different times and places.
Looking at an evolutionary perspective, specialised forms of skeletal and cardiac muscles predated the divergence of the vertebrate / anthropod evolutionary line. This indicates that these types of muscle developed in a common ancestor 700 million years ago (mya).
The next blog post regarding this broad topic will discuss the real-life contexts and purposes and types of motion, as well as the evolutionary, philosophical, social and political perspectives.
