Bioenergetic basis of skeletal muscle fatigue

Energetic demand from high-intensity exercise can easily exceed ATP synthesis rates of mitochondria leading to a reliance on anaerobic metabolism. The reliance on anaerobic metabolism results in the accumulation of intracellular metabolites, namely inorganic phosphate (P_i) and hydrogen (H⁺), that are closely associated with exercise-induced reductions in power. Cellular and molecular studies have revealed several steps where these metabolites impair contractile function demonstrating a causal role in fatigue. Elevated P_i or H⁺ directly inhibits force and power of the cross-bridge and decreases myofibrillar Ca²⁺ sensitivity, whereas P_i also inhibits Ca²⁺ release from the sarcoplasmic reticulum (SR). When both metabolites are elevated, they act synergistically to cause marked reductions in power, indicating that fatigue during high-intensity exercise has a bioenergetic basis.