from Guyton and Hall textbook of medical physiology, 4th South Asia edition write a 15 mark long answer on Name the muscle proteins. Describe the sliding filament theory of skeletal muscle contraction. What is the aetiological basis of Myasthenia Gravis? (2+8+5)

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Long Answer: Muscle Proteins, Sliding Filament Theory of Skeletal Muscle Contraction, and Myasthenia Gravis (15 Marks)

Part 1: Muscle Proteins (2 Marks)

Skeletal muscle filaments are composed of two types: thick filaments (myosin) and thin filaments (actin, with associated regulatory proteins).

Thick Filament: Myosin

Each myosin molecule (mol. wt. ~480,000) consists of six polypeptide chains:

Two heavy chains (mol. wt. ~200,000 each) - wind spirally around each other to form the double-helix tail. At one end, each chain folds into a globular myosin head.
Four light chains (mol. wt. ~20,000 each) - two per head; help regulate head function.

Each myosin filament is assembled from 200 or more individual myosin molecules. The tails bundle together to form the filament body, while the heads project outward as cross-bridges. Each cross-bridge has two hinges - one at the junction of arm and body, another between head and arm - allowing flexible movement. The heads also function as ATPase enzymes, cleaving ATP to energize the power stroke.

Thin Filament: Three Proteins

1. Actin (F-actin) The backbone is a double-stranded F-actin helix, each strand composed of polymerized G-actin molecules (mol. wt. ~42,000). One ADP molecule is attached to each G-actin monomer; these ADP-bearing sites are the active sites where myosin cross-bridges attach. Active sites are staggered, with one every ~2.7 nm along the filament. Each actin filament is ~1 micrometer long; its base is inserted into the Z disk.

2. Tropomyosin Each molecule has a mol. wt. of ~70,000 and a length of ~40 nm. Tropomyosin strands are wrapped spirally around the sides of the F-actin helix. In the resting state, tropomyosin lies over the active sites on actin, physically blocking myosin cross-bridge attachment and thus preventing contraction.

3. Troponin (Regulatory Complex) Attached intermittently along the tropomyosin strands. It is a complex of three subunits:

Troponin I - strong affinity for actin
Troponin T - affinity for tropomyosin; anchors the complex
Troponin C - strong affinity for Ca²⁺ (binds up to 4 Ca²⁺ per molecule); triggers the conformational change initiating contraction

Guyton and Hall Textbook of Medical Physiology, pp. 93-95

Part 2: Sliding Filament Theory of Skeletal Muscle Contraction (8 Marks)

Basic Concept

Muscle contraction occurs by a sliding filament mechanism: actin (thin) filaments slide inward among myosin (thick) filaments, pulling the Z disks toward each other and shortening the sarcomere. Critically, neither the actin nor the myosin filaments change in length - only their degree of overlap changes.

Structural Basis: The Sarcomere

The sarcomere (distance between two successive Z disks, ~2 µm at full contraction) is the functional unit:

A band (dark): contains myosin filaments + overlapping ends of actin filaments (anisotropic)
I band (light): contains only actin filaments (isotropic)
Z disk: anchors actin filaments; filaments extend in both directions
H zone: central region of A band with myosin only, no actin overlap
M line: central point of myosin filament, no cross-bridges

During contraction, the I band and H zone shorten while the A band remains constant - confirming that filaments slide rather than shorten.

Sequence of Events in Contraction

The initiation and execution of muscle contraction proceeds in the following steps (Guyton's 8-step sequence):

An action potential travels along a motor nerve to its endings on muscle fibers.
At each nerve ending, a small amount of acetylcholine (ACh) is secreted.
ACh acts on the muscle fiber membrane, opening acetylcholine-gated cation channels through protein molecules in the membrane.
Opening of these channels allows rapid diffusion of Na⁺ ions into the muscle fiber, causing local depolarization - this triggers opening of voltage-gated Na⁺ channels and initiates an action potential at the motor end plate.
The action potential travels along the muscle fiber membrane in both directions to the fiber ends.
The action potential depolarizes the muscle membrane; electrical current flows through the center of the fiber via T tubules (transverse tubules), causing the sarcoplasmic reticulum to release large quantities of stored Ca²⁺.
Ca²⁺ ions initiate attractive forces between actin and myosin filaments, causing them to slide alongside each other - the basis for muscle contraction.
After a fraction of a second, Ca²⁺ is pumped back into the sarcoplasmic reticulum by the SERCA (Sarcoplasmic Reticulum Ca²⁺-ATPase) pump; removal of Ca²⁺ causes contraction to cease (muscle relaxes).

Excitation-Contraction Coupling

The action potential spreads into the muscle fiber interior through T tubules (transverse tubules), which penetrate from the surface to the deep interior. The T tubule action potential is sensed by dihydropyridine receptors (DHPR), which are linked to ryanodine receptor (RyR) channels in the adjacent terminal cisternae of the sarcoplasmic reticulum. DHPR activation triggers opening of RyR channels, releasing Ca²⁺ into the sarcoplasm surrounding the myofibrils.

The normal resting Ca²⁺ concentration (<10⁻⁷ molar) is too low to elicit contraction. When released Ca²⁺ raises this concentration, contraction is initiated.

Molecular Mechanism: The Walk-Along (Ratchet) Theory

Step 1 - Inhibition at rest: In the relaxed state, the troponin-tropomyosin complex covers the active sites on actin filaments, preventing myosin head attachment.

Step 2 - Ca²⁺ activation: When Ca²⁺ binds to Troponin C, the troponin complex undergoes a conformational change that tugs tropomyosin deeper into the groove between the two actin strands, uncovering the active sites on actin.

Step 3 - Cross-bridge cycling (Power Stroke): The sequence of molecular events is:

Step	Event
1	Myosin head binds ATP; ATPase cleaves it to ADP + Pᵢ (stored like a cocked spring); head extends perpendicularly toward actin
2	Activated actin sites attract the myosin cross-bridge heads; head attaches to active site on actin
3	Attachment causes conformational change in the head; head tilts toward the arm - this is the power stroke, dragging actin ~10 nm toward the center of the myosin filament
4	ADP and Pᵢ are released from the head
5	A new ATP molecule binds to the head, causing detachment from actin
6	New ATP is cleaved, cocking the head back to perpendicular position, ready for the next cycle
7	Head attaches to a new, further active site on actin and repeats the power stroke

This repeating cycle is called the walk-along (or ratchet) theory. Each cross-bridge operates independently, with different cross-bridges in different phases at any one moment - producing smooth, continuous contraction.

Relaxation

When nerve stimulation ceases:

No new action potentials are generated
Ca²⁺ is actively pumped back into the sarcoplasmic reticulum by SERCA
Calsequestrin (inside the reticulum) binds and stores Ca²⁺
Ca²⁺ dissociates from Troponin C
Tropomyosin re-covers the active sites on actin
Cross-bridge cycling stops and the muscle returns to the resting state

Length-Tension Relationship

The tension developed by a contracting muscle is directly proportional to the degree of overlap between actin and myosin filaments:

At sarcomere length ~2.0-2.2 µm: maximum overlap, maximum tension
If sarcomere is overstretched (>3.6 µm): no overlap, zero tension
If overshortened (<1.6 µm): actin filaments from opposite sides collide, tension falls

Guyton and Hall Textbook of Medical Physiology, pp. 92-97, 107-110

Part 3: Aetiological Basis of Myasthenia Gravis (5 Marks)

Definition and Incidence

Myasthenia Gravis (MG) is a disorder characterized by progressive muscle weakness due to impaired neuromuscular transmission. It occurs in approximately 1 in every 20,000 persons.

Pathophysiology: Autoimmune Destruction of ACh Receptors

MG is an autoimmune disease in which the patient's immune system produces antibodies directed against the nicotinic acetylcholine receptors (nAChRs) at the postsynaptic neuromuscular junction.

The normal adult nAChR is a pentameric protein complex (mol. wt. ~275,000) composed of two alpha (α), one beta (β), one delta (δ), and one epsilon (ε) subunit. Two ACh molecules must bind to the two alpha subunits simultaneously to open the ion channel.

In MG:

Anti-AChR antibodies (IgG class) bind to the alpha subunits of postsynaptic receptors
These antibodies block ACh binding, accelerate receptor internalization and degradation, and activate complement-mediated destruction of the postsynaptic membrane (simplifying or destroying the normal subneural cleft folds)
The number of functional AChRs is drastically reduced
The resultant end plate potentials (EPPs) are mostly too weak to reach the threshold for opening voltage-gated Na⁺ channels
No muscle fiber action potential is generated - muscle fiber depolarization does not occur
Clinically: progressive fatigable weakness, especially of extraocular, facial, bulbar, and proximal limb muscles

Role of the Thymus

In about 75% of MG patients, the thymus is abnormal:

~65% show thymic hyperplasia (germinal center formation)
~10-15% have a thymoma (thymic tumor) The thymus is thought to be the primary site of sensitization, as it contains myoid cells bearing AChR-like antigens that may trigger the autoimmune response.

Consequences and Clinical Correlation

Since each nerve impulse normally releases ~125 ACh vesicles and each vesicle contains ~10,000 ACh molecules, with reduced receptor numbers, the safety factor of neuromuscular transmission is lost. With repetitive stimulation, the already-reduced EPPs become progressively smaller (decremental response on electromyography), explaining the hallmark feature of fatigable weakness.

Treatment Rationale (reflecting aetiology)

Anticholinesterase drugs (e.g., neostigmine, pyridostigmine): inhibit acetylcholinesterase in the synaptic cleft, allowing larger amounts of ACh to accumulate and compete with antibodies for the residual receptors - this can restore function for several hours
Immunosuppression (corticosteroids, azathioprine): reduces antibody production
Plasmapheresis/IVIG: removes circulating anti-AChR antibodies
Thymectomy: removes the source of autosensitization

Guyton and Hall Textbook of Medical Physiology, pp. 107-108, 470

Summary Table

Component	Key Points
Muscle proteins	Myosin (thick - 2 heavy + 4 light chains, ATPase head); Actin (thin - F-actin + G-actin + ADP active sites); Tropomyosin (covers active sites at rest); Troponin I/T/C (Ca²⁺ sensor)
Sliding filament	Sarcomere shortens; A band constant; I band + H zone shorten; cross-bridge walk-along ratchet powered by ATP; Ca²⁺-troponin C-tropomyosin cascade uncovers actin sites
Myasthenia Gravis	Autoimmune IgG anti-nAChR antibodies; block + degrade postsynaptic receptors; EPPs too weak to fire AP; fatigable weakness; thymus role; treated with neostigmine/immunosuppression

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