Which statement is NOT typically listed as a principal mechanism of skeletal muscle fatigue?

• A. Metabolic substrate depletion and accumulation of metabolic byproducts.
• B. Impairment of EC coupling and Ca2+ handling.
• C. Ionic imbalances.
• D. Neural fatigue is the sole cause of fatigue.

Answer: (D)

The idea being tested is that muscle fatigue is caused by several interacting peripheral processes, not by a single factor. In skeletal muscle, fatigue commonly involves depletion of energy substrates and buildup of metabolic byproducts that slow metabolism and cross-bridge cycling; impairment of excitation-contraction coupling and calcium handling that reduces the amount of calcium available to trigger contraction; and ionic imbalances that alter membrane excitability and signaling. The statement proposing neural fatigue as the sole cause isn’t aligned with how fatigue is understood, because neural factors can influence fatigue, but fatigue also arises from these peripheral mechanisms. So the other mechanisms are the ones typically recognized as the main contributors, while neural fatigue is not considered the sole cause.