Sarcomere

Structure of the Sarcomere

A sarcomere is a segment of a myofibril located between two adjacent Z-lines (Z-discs). Thin filaments attach to these borders. Hundreds and thousands of such units are arranged sequentially within a single myofibril.

Main Structural Elements:

• Myosin — thick filaments. They possess a mobile head with enzymatic activity (ATPase).
• Actin — thin filaments attached to the Z-discs. They contain binding sites for myosin.
• Tropomyosin — thin filaments of a regulatory protein on the actin surface.
• Troponin — a regulatory protein located on actin; at rest, it blocks the interaction between actin and myosin.
• T-tubules — a system of transverse tubules that conduct excitation deep into the cell.

Fulfilling a structural ratio, thin to thick filaments are present in an approximately 4:1 ratio. In cross-section within the overlap zone, a strict hexagonal packing is observed: 6 thin filaments are grouped around one thick filament, and 3 thick filaments around one thin filament.

Topography and Zones (from edge to edge):

1. Z-line — the border of the sarcomere.
2. I-band half (light) — contains only thin myofilaments.
3. Dark part of the A-band — the overlap zone containing both thick and thin filaments.
4. H-zone — a light band in the center of the A-band, containing only thick myofilaments. The M-line runs through the middle.
5. Dark part of the A-band.
6. I-band half (light).
7. Z-line — the opposite border.

It is this zonal distribution that creates optical inhomogeneity. The alternation of light I-bands and dark A-bands creates the characteristic cross-striation visible under a light microscope in an entire muscle fiber.

Mechanism of Muscle Contraction

The mechanism of sarcomere function is based on the sliding filament theory. Driven by $Ca^{2+}$ ions, filament sliding occurs.

Stages and Band Dynamics:

• The myosin head performs a power stroke.
• The actin filament is pulled toward the center of the sarcomere, sliding along the myosin filament.
• Z-discs move closer together, and the overall length of the sarcomere decreases.
• Thin filaments penetrate deeper between the thick ones: light I-bands and the H-zone narrow, while the dark parts of the A-band (overlap zones) widen.
• The total width of the A-band remains unchanged because the length of the thick filaments does not change.

Maximum contraction limit is reached when the I-bands completely disappear and the thick filaments abut the Z-lines. At resting dimensions (I-band — 0.8 µm, A-band — 1.5 µm), the muscle can shorten by approximately 35% of its length.

Length-Tension Relationship:

• With excessive stretch, the number of cross-bridges between actin and myosin drops, decreasing contraction force.
• With no load (over-shortening), actin filaments overlap each other, the number of effective bridges also drops, and the contraction force decreases.

Clinical Significance: Hypertrophic Cardiomyopathy

In hypertrophic cardiomyopathy (HCM), pathogenic variants in sarcomeric protein genes are frequently encountered. In 15–20% of cases, HCM is caused by pathogenic variants in genes encoding cytoskeletal proteins, ion channels, Z-disc components, and other intracellular structures.

Pathogenesis:

1. Calcium homeostasis is disrupted, and myofilament sensitivity to $Ca^{2+}$ increases.
2. Contractility impairment occurs: sarcomere contraction force during systole increases, while relaxation during diastole decreases.
3. Energy deficit develops due to increased ATP demand by the cardiomyocyte.
4. Intracellular processes malfunction, and compensatory embryonic hypertrophic growth programs are reactivated.
5. At the cellular level, synthesis of embryonic sarcomeric protein isoforms increases, kinase signaling cascades are activated, fibroblasts proliferate and transform into myofibroblasts, and collagenolysis is imbalanced.

Genetic Features: Most pathogenic variants are unique: they have been described only once or in isolated patients. The frequency of any specific substitution among all HCM causes does not exceed 1%. In 5–7% of cases, multiple mutations occur: the presence of 2, 3, or more pathogenic variants. Most commonly, these are combinations of mutations in sarcomeric protein genes. They are characterized by an earlier onset (often in childhood), marked interventricular septal hypertrophy, and a high risk of sudden cardiac death.