Understanding muscle physiology and its function

Structure of a Cell:

The human body is comprised of 4 cell types epithelial cells, muscle cells, nerve cells and connective tissue cells. Each cell type are found in all cells. They have their unique modifications to components that give the cell type its unique attributes.

Name of Structure	Function in Muscle
Nuclei	The nuclei contain all genetic material (DNA), allowing for replication, growth, and repair of cell structures.
Myosin and Actin	These protein filaments (myofilaments) are the contractile proteins responsible for contraction of a muscle cell .Myosin has a thicker of the two structures with globular heads. It attachs to binding sites on actin.	.
Sarcoplasmic Reticulum	This organelle forms a network of reservoirs around the myofilaments, supplies the cell with nutrients, and releases calcium as part of the contraction process.
Mitochondria	These generate most of the supply of ATP by way of aerobic metabolism which breakdowns carbohydrates and fatty acids for fuel.
Sarcoplasm	This is the fluid within the cell in which various particles and organelles are suspended.This liquid is primarily comprised of water and glycogen.
Sarcolemma (Myolemma)	This is the cell’s membrane, forming a barrier between extracellular and intracellular compartments.T-tubules penetrate the sarcolemma to allow for a transport of nutrients into and out of the cell.
Sarcomere	A segment of a muscle cell, repeated longitudinally, composed of parallel contractile filaments (actin and myosin) suspended between two “Z-line” .This is the smallest functional unit of a muscle cell.
Titin	A specialized protein within a muscle cell that extends from the “Z band” to the middle of a sarcomere (M-Line).This protein helps in the alignment of actin and myosin and adds to the durabilitiny in elasticity  of a muscle cell.
Microtubule	The microtubule in muscles cells is modified to help in stability and alignment of the actin and myosin filaments.

“Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. Blausen.com staff (2014).

Muscle Tissue Traits :

All cells have “traits”, some of the characteristics that make a muscle cell unique are responsiveness, conductivity, contractility, extensibility, and elasticity. These traits are explained in further detail below:

1. Responsiveness: The ability of a cell to respond or react to stimuli.
2. Excitability: The ability of a cell to change in membrane conductance as a response to stimulation. 
3. Conductivity: The stimulation of a motor endplate results in a change in cell membrane polarity that rapidly propagates along the entire length of the muscle cell (origin to insertion).
4. Contractility: Muscle cells are unique where they can shorten when stimulated.  This is due to the organized arrangement of myofilaments.
5. Extensibility: This is the ability of a cell to be stretched or lengthened without damage. 
6. Elasticity: It is the ability of a cell to return to its resting length after stretched.

Stimulus to Muscle Cell:

The next section will focus on changes occur at the cellular level in a muscle. An action potential goes from motor neuron to simulating the sarcolemna. It is conducted through the microtubules and the myofibrils which are divided into sarcomere.

Neural Activation: The excitation of a muscle cell starts at a motor neuron (found in the brain stem or spinal cord). An impulse is generated when the motor neuron is sufficiently stimulated till get the results in an “action potential.” The action potential is conducted along the length of an axon to the neuromuscular junction.

Note: Relaxation occurs due to the presence of the basal lamina in the synaptic cleft which contains an enzyme called acetylcholinesterase.  This enzyme is responsible for the breakdown of ACh. The breakdown of ACh returns the cell to a relaxed state.  

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Muscles will contract or relax when they receive signals from the nervous system. The  signal exchange at the neuromuscular junction site. The steps of this process in vertebrates occur as follows: (1) The action potential reaches the axon terminal. (2) Voltage-dependent calcium gates open, allowing calcium to enter the axon terminal. (3) Neurotransmitter vesicles fuse with the presynaptic membrane and acetylcholine (ACh) is released into the synaptic cleft via exocytosis. (4) ACh binds to postsynaptic receptors on the sarcolemma. (5) This binding causes ion channels to open and allows sodium ions to flow across the membrane into the muscle cell. (6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which travels to the myofibril and results in muscle contraction. Labels: A: Motor Neuron Axon B: Axon Terminal C. Synaptic Cleft D. Muscle Cell E. Part of a Myofibril

  Excitation-Contraction Coupling: 

1. Action potential conducts down T-tubules
2. Opens voltage-regulated calcium channels
3. Calcium is released and binds to troponin
4. The change in the shape of the troponin-tropomyosin complex exposes binding sites.

Note: Troponin is a protein that is bound to tropomyosin which wraps around actin (the thin filament).

Actin (Thin Filament), troponin, tropomyosin and myosin – Häggström, Mikael (2014). “Medical gallery of Mikael Häggström 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436.

Power Stroke: The myosin must be bound to an adenosine triphosphate (ATP) molecule.  followed by it is then broken down to adinosine diposphate (ADP) which “cocks” the myosin head into an extended position.  If there is an active site available on troponin, the myosin head will bind to it, this is known as “cross-bridging.” The release of the ADP results in the “flexing” of the myosin head which pulls actin with it.  This forceful pull on actin by myosin is known as the “power stroke.” The myosin head stays bound to troponin until more ATP is available to bind to the myosin head. 

1. ATP binds to Myosin
2. Break down ATP becomes ADP and extends the myosin head
3. The myosin head binds to an available binding site on troponin
4. Release of ADP results in flexing of the myosin head
5. Flexing the myosin head pulls actin resulting in a power stroke
6. ATP binds to myosin releasing the head from troponin
7. Process starts over at a binding site further down actin.

Note:

• The specific number of  myosin heads that attach to actin binding sites (cross-bridging) at any one time dictates the amount of force which can be produced by the muscle cell (2).
• This process occurs in cyclical fashion, attaching, flexing and detaching, to produce (concentric contraction), reduce (eccentric contraction), or maintain (isokinetic) force during movement.

 Sliding Filament Theory: 

We have covered the process from impulse (intent resulting in an action potential) to conformational (shape) changes in contractile proteins, resulting in a “power stroke.”  Sliding filament theory explains the organization and structure of these contractile proteins. In the image below, note the thick myosin filaments (horizontal and red) and the thin actin filaments (horizontal in blue).  The bumps on the myosin proteins represent the myosin heads.  This is the portion of myosin that binds to troponin (of the troponin-tropomyosin complex) embedded on the actin filaments.  At either end of the myosin proteins, note the “z-disks” (vertical pink line).  This represents a protein structure that borders and separates two adjacent sarcomere. When contraction is initiated, the synchronized “power strokes” (like synchronized rowers in a race) “pull” on actin, sliding the filaments across one another, and pulling the z-disks closer to one another. consider how many microscopic sarcomere must be connected in series to span the full length of a muscle fiber, and how many parallel tubes of sarcomere (myofibril) are then clustered into muscle cells. Muscle cells are then clustered into fascicles (fibers), finally fascicles into muscle bellies.  It is not hard to imagine how a small, seemingly insignificant force generated by a single protein, is multiplied millions of times, to generate significant force every time you contract a muscle. The reason muscle cells are so unique in their ability to contract and produce force, is this repeated pattern of parallel proteins throughout the entirety of a muscle cell.

 Multiplication by Organization:

1. Each myosin filament has multiple heads capable of producing a power stroke
2. Approximately 6 actin, with multiple binding sites, surround each strand of myosin filament
3. There are many parallel myosin and actin per myofibrile (tubes of contractile proteins in honeycomb-like arrangement)
4. There are many sarcomere in series per myofibril along the length of a muscle cell
5. Muscle cells (myocytes) are comprised of many myofibril
6. There are many muscle cells per fascicle
7. Muscles are generally comprised of many fascicles

When using this image in external works, it may be cited as follows:”Medical gallery of David Richfield”. WikiJournal of Medicine 1 (2). By David Richfield (User:Slashme)DOI:10.15347/wjm/2014.009. ISSN 2002-4436. – Own work, CC BY-SA 3.0 https://commons.wikimedia.org/w/index.php?curid=2264027

Influence of sliding filament theory on our understanding of motion

The number of cross-bridges, the amount of over-lap of actin and myosin (A-band) is correlated with the amount of force a muscle can produce. Changes in sarcomere length results in a decrease in the number of cross-bridges.  This results in a relationship between length and tension discussed below under “Length/Tension Relationship.”

There are limits to the capacity of a muscle cell to shorten and lengthen, and produce force at the extreme ends of these range.  This is sometimes referred to as active insufficiency (too short) and passive insufficiency.

How the motor unit recruit?

When an action potential reaches the end of an axon it spreads out over many terminal branches. Each branch stimulates a different muscle cell.    In essence, a motor neuron and all of the muscle cells that innervates function as a unit. A motor neuron, axon (nerve fiber), terminal branches and all of the muscle cells (muscle fibers) it innervates are known as a motor unit. 

1. Single motor neuron and axon
2. Many terminal branches
3. All innervating a different muscle cell
4. Stimulating a motor unit

How to determined Endurance:

1. Available ATP
2. The number and coordination of motor units working “in-shifts”

Note: In later lessons we will discuss how muscle cells adapt to exercise to enhance strength, endurance and power.

    Why is this information important: 

It is important to be aware of muscle cell physiology to inform the decision making process during interventions for rehab, fitness or performance.  For example, the knowledge that available ATP is necessary for continued contraction may influence our understanding of research on energy systems and acute variables (reps, load, tempo).  The physiology of contraction may also help in understanding how creatine phosphate supplementation plays a role in augmenting training.

Second, knowledge of physiology becomes a misinformation filter. Too many myths, misguided recommendations and physiologically impossible promises are peddled to the professional and consumer alike .  Having a strong foundation of physiology may help in deciding which recommendations have potential to work and which do not.

To sum up, understanding this process should bring a feeling of shear amazement at the intricacy of the human body.  consider that this happens many times per second, at every muscle cell of every motor unit, of every muscle you recruit at every joint, every time.

Stimulus (intent, reflex, motor program, etc)

Action potential at motor neuron

Conducted by axon to synapse

ACh released into the neuromuscular junction

ACh binds to receptors on motor end plate of the muscle cell

Sodium ion channels open on the motor endplate

Action potential is proprogated across sarcolemna

Action potential conducts down T-tubules

Opens voltage-regulated calcium channels

Calcium is released and binds to troponin

The change in the shape of the troponin-tropomyosin complex exposes binding sites

ATP binds to Myosin

Hydrolized ATP becomes ADP and extends the myosin head

The myosin head binds to an available binding site on troponin

Release of ADP results in flexing of the myosin head

Flexing the myosin head pulls actin resulting in a power stroke

ATP binds to myosin releasing the head from troponin

Process starts over at a binding site further down actin.

This step is the multiplied by the number of binding sites on each protein, the number of proteins in each sarcomere, the number of proteins in parallel in each myofibrile, and the number myofibrile in each muscle cell.

Force output is then multiplie again, and calibrated for function, by the number of cells in the motor unit recruited, and the number of motor units recruited.

Note: Every step represents years of work from incredible minds, and pivotal peer-reviewed publications.

Length-Tension Relationship:

The amount of over-lap between actin and myosin filaments (A-band) is correlated with number of cross-bridges that can form moreover the amount of force that can be generated. A muscle cell will produce less force when approaching a maximally shortened length. This results in a “upside-down U” shaped relationship between length and tension, with most muscles producing the most force close to their resting length.

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Length/Tension Relationship: the “active” portion of this graph is explained by the interaction between actin and myosin described above, the passive relationship is as if the muscle was being stretch and resistance to extensibility is being imparted by proteins like titin and the connective tissue layers. By Mokele [Public domain], via Wikimedia Commons

     Referance:

Haff, G.G., Triplett, N.T. (2016). Essentials of Strength and Conditioning Training. (4th Ed.). Human Kinetics; Champaign, Il.

Saladin, K. (2012). Anatomy & Physiology: The unity of form and function. (6th ed.). New York: McGraw-Hill.

Lodish, H., et al. (2000). Molecular Cell Biology. (4th ed.). New York: W.H. Freeman.

Grosberg, A., et al. (2011). Self-organization of muscle cell structure and function. PLoSOne. http://doi.org/10.1371/journal.pcbi.1001088.

Bodriau, S., Vincent, M., Cote, C.H., & Rogers, P.A. (1993). Cytoskeletal structure of skeletal muscle: identification of an intricate exosarcomeric microtubule lattice in slow-and fast-twitch muscle fibers.

Schoenfield, B. (2016). Science & Development of Muscle Hypertrophy. Human Kinetics; Champaign, Il.

Tiidus, P. (2008). Skeletal Muscle Damage and Repair. Human Kinetics; Champaign, Il.

Cooper, G.M. (2000). The Cell: A Molecular Approach. (2nd ed.). Massachusetts: Sinauer Associates.