A researcher isolates a single intact skeletal muscle fiber and stimulates it at a high frequency with a large stimulating electrode to induce fatigue. Which of the following is the primary mechanism of this fatigue?

• A Accumulation of extracellular potassium causing depolarization block
• B Depletion of glycogen stores within the muscle fiber
• C Failure of neuromuscular transmission at the motor end plate
• D Accumulation of inorganic phosphate from ATP hydrolysis impairing cross-bridge force and SR calcium release ✓

Explanation

During high-frequency stimulation of an isolated skeletal muscle fiber, fatigue is primarily caused by accumulation of inorganic phosphate (Pi) from ATP hydrolysis. Pi enters the sarcoplasmic reticulum and precipitates with Ca2+, reducing Ca2+ release, and also directly reduces myofibrillar Ca2+ sensitivity and cross-bridge force. Since the fiber is directly stimulated (large electrode), neuromuscular transmission is bypassed, ruling out C. Glycogen depletion occurs over longer durations.

Reference: Ganong's Review of Medical Physiology, 26th ed.

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