Anatomy of Skeletal Muscle

Each skeletal muscles are composed of numerous muscle fibers. Each muscle fiber contains following structures:

1. Sarcolemma: Plasma membrane of a muscle fiber that forms T tubules
2. Sarcoplasm: Cytoplasm of a muscle fiber that contains organelles, including mitochondria
3. Glycogen: A polysaccharide present in sarcoplasm that stores energy for muscle contraction
4. Myoglobin: A red pigment present in sarcoplasm that stores oxygen for muscle contraction
5. T tubule: Extension of the sarcolemma that extends into the muscle fiber and conveys impulses that causes Calcium to be released from the sarcoplasmic reticulum
6. Sarcoplasmic reticulum: The smooth endoplasmic reticulum (ER) of a muscle fiber that stores calcium
7. Myofibril: A bundle of myofilaments that contract
8. Myofilament: Actin and myosin filaments whose structure and functions account muscle striations and contractions

A sarcomere extends between 2 dark lines called Z lines. A sarcomere contains 2 types of protein myofilaments:

1. Thick filaments: made up of several molecules of myosin (golf shaped) with cross bridges (double globular head)
2. Thin filaments: made up of 2 interwining strands of actin along with tropomyosin and troponin

The I band is light colored because it contains only actin filaments attached to Z line. The dark regions of A band (Anisotropic) contain overlapping actin and myosin filaments and its H zone has only myosin filaments. I bands are isotropic to polarized light while A bands are anisotropic.

When sarcomere shortens, the actin (thin) filaments slide pas the myosin (thick) filamets and approach one another. This causes I band to shorten and H zone to almost or completely disappear. During the sliding process, the sarcomere shortens even though the filaments themselves remain the same length.

What keeps the myosin and actin filaments in place?
Titin filamentous molecules (one of the largest protein molecules in the body and are springy in nature)

Physiology of Skeletal muscle contraction

Neuromuscular Transmission:

Muscle fibers are innervated by motor neurons and the axon of one motor neuron has several branches and can stimulate from a few to several muscle fibers of a particular muscle. Each brach of the axon ends in an axon terminal that lies in close proximity to the sarcolemma of a muscle fiber. A small gap called a synaptic cleft, separates the axon bulb from the sarcolemma. This entire region is called a neuromuscular junction. Axon terminals contains synaptic vesicles that are filled with the neurotransmitter Acetylcholine.

1. Action Potential (AP) in motor nerve axon terminal
2. Opening of voltage gated Ca2+ channels and entry of Calcium in axon terminal
3. Calicum activates calmodulin which activates protein kinase
4. Protein kinase phosphrylates synapsins which aid in the fusion of synaptic vesicles
5. Diffusion of ACh from vesicles into synaptic cleft
6. Attachment of ACh with receptors (with 5 subunits) in the sarcolemma
7. Opening of voltage gated Na+ channel and Na+ entry in the sarcolemma
8. End plate potential
9. AP in sarcolemma
10. Hydrolysis of Ach by cholinesterase

Molecular mechansim of muscle contraction:

Actin filaments slide inward among the myosin filaments due to forces generated by interaction of the cross bridges from the myosin filaments with the actin filaments. Under resting conditions, these forces are inactive, but when an AP travels along the muscle fiber, this causes the sarcoplasmic reticulum to release large quantities of Ca2+ that rapidly surround myofibrils. The Ca2+ activate the forces between the myosin and actin filaments and contraction begins. This energy for contraction comes from ATP molecule which is degraded to ADP.

Myosin filament:

• composed of multiple myosin molecules (>200)
• 2 heavy chains wrap spirally around each other to form a double helix, which is called the tail of myosin molecule
• one end of each of these chains is folded bilaterally into a globular polypeptide structure called myosin head
• 4 lighy chains, 2 to each head (help to control the function of head during muscle contraction)
• Tails of myosin molecules bundled together to form body of the filament; many heads being outward to the sides of the body
• Part of body of myosin molecule hangs to the side along with the head outward from the body (protruding arms and heads together are called cross-bridges)
• Each cross-bridge is flexible at 2 points called hinges : one where arm leaves the body and other where head attaches to the arms
• There are no cross-bridge heads in the very center of myosin filament for a distance of about 0.2 micrometer because the hinged ar,s extend away from center
• ATPase enzyme in the myosin head allows the head to cleave ATP

Actin filament:

• backbone of actin filament is a double stranded F-actin protein molecule (2 strands wound as helix)
• each strand of double F-actin helix is composed of polymerized G-actin molecules
• attached to each one of the G-actin molecules is one molecule of ADP (active sites on actin filaments with which the cross-bridges of myosin filaments interact)
• bases of actin filaments are inserted strongly into the Z discs; the ends of filamets protrude in both directions to lie in the spaces between the myosin molecules
• Tropomyosin molecules wrapped spirally around the sides of the F-actin helix
• In the resting state, tropomyosin molecules lie on top of the active sites of the actin strands
• Troponin attached intermittently along the sides of the tropomyosin molecules
• Troponin are complexes of 3 loosely bound protein subunits
  • troponin I : greater affinity for actin
  • troponin T: greater affinity for tropomyosin
  • troponin C: greater affinity for Ca2+ ions

The active sites on the normal actin filament of the relaxed muscle are inhibited or physically covered by the troponin-tropomyosin complex. Consequently, the sites cannot attach to the heads of the myosin filaments to cause contractions. When Ca2+ ions combine with troponin C, each molecule of which can bind strongly with upto 4 Ca2+ ions, the troponin complex undergoes a conformational change that in some way tugs on the tropomyosin molecule and moves it deeper into the groove between the 2 actin strands. This uncovers the active sites of the actin allowing theses to attract myosin cross-bridge heads and contraction proceeds.

“Walk along” theory of contraction:

When a head attaches to an active site, this attachment simultaneously causes profound changes in the intramolecular forces between the head and arms of its cross-bridge. The new alignment of forces causes the head to tilt toward the arm and to drag the actin filament along with it. This tilt of the head is called the powerstroke. Immediately after tilting, the head automatically breaks away from the active site and returns to its extended direction. In this position, it combines with a new active site farther down along the actin filament causing new powerstroke.

Thus, the heads of the cross-bridges bend back and forward and step by step walk along the actin filament, pulling the ends of 2 succesive actin filaments toward the center of the myosin filament. Each one of the cross-bridges is believed to operate independently of all others, each attaching and pulling in a continuous repeated cycle.

Heance, greater the number of cross bridges in contact with actin filament, greater willl be the force of contraction.

Fenn Effect:

Large amounts of ATP are cleaved to form ADP during contraction process and as the work performed by the mucle increases, the amount of ATP cleaved will also increase.

Role of ATP:

Before contraction, heads of cross-bridges bind with ATP. ATPase activity of head cleaves ATP leaving ADP and phosphate ion bound to head.

When troponin-tropomyosin complex binds with Ca2+ ions, active sites on actin filament are uncovered and the myosin heads then bind with these.

Power stroke is activated by the energy already stored, like a “cocked” spring, by the conformational change that occured in the head when ATP molecule was cleaved earlier.

Tilted head of cross-bridge allows release of ADP and phosphate ion that were previously bound to the head. At the site of release of ADP, a new molecule of ATP binds. This causes detachment of head from actin.

A new power stroke after the detachment of head from the actin and cleavage of new ATP molecule.

The process repeats continuously until the actin filaments pull the Z membrane up against the ends of the myosin filaments or until the load on the muscle becomes too great for further pulling to occur.

Muscle relaxation:

1. Calcium is removed by Ca2+ pump (Ca2+-Mg2+ ATPase) by pumping back to sarcoplasmic reticulum
2. Troponin returns to original site
3. Requires ATP and is an active process

Denervation Hypersensetivity:

Denervation of mucle –> increased ACh receptors all over sarcolemma –> even low ACh leads to muscle contraction –> gradually leads to enervation atrophy

Rigor Mortis:

• continued contraction in the absence of any stimulation due to failure of relaxation after death
• no supply of ATP –> Ca2+ cannot be removed from the cytosol

References:

• Understanding Human Anatomy and Physiology – Mcgraw and Hill
• Textbook of Medical Physiology – Guyton and Hall
• Essentials of Medical Physiology – Mahapatra