Duchenne muscular dystrophy is caused by dystrophin deficiency. Dystrophin connects the intracellular actin cytoskeleton to the extracellular matrix via the dystrophin-associated protein complex (DAPC). The primary pathological consequence of dystrophin loss is:

• A Absence of dystrophin directly impairs actin-myosin crossbridge cycling, reducing force generation and causing muscle fiber atrophy
• B Loss of DAPC disrupts NOS localization, reducing nitric oxide production and impairing functional hyperemia during exercise
• C Loss of mechanical continuity between the sarcomere and sarcolemma causes membrane microtears during contraction, allowing Ca²⁺ influx that activates calpains and triggers necrosis ✓
• D Dystrophin absence destabilizes voltage-sensitive phosphatase in the t-tubule, impairing excitation-contraction coupling

Explanation

Dystrophin's primary mechanical role is to transmit contractile force from the intracellular actin to the extracellular matrix (laminin-2), distributing stress across the sarcolemma. Without dystrophin, the sarcolemma is fragile and develops microtears during eccentric contractions. These membrane disruptions allow uncontrolled Ca²⁺ influx from the extracellular space, activating calcium-dependent neutral proteases (calpains 1 and 3) and triggering mitochondrial permeability transition pore opening, culminating in necrosis. Repeated cycles of necrosis and incomplete regeneration eventually exhaust the satellite cell pool. While neuronal NOS (nNOS) is also displaced from the sarcolemma in DMD, the primary pathological initiator is mechanically induced Ca²⁺ overload.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.