Bioenergetic basis of skeletal muscle fatigue

•The reliance on anaerobic metabolism causes fatigue during high-intensity exercise.•Metabolic pathways maintain ATP at levels that do not impair contractile function.•Intracellular homeostasis is disrupted by metabolite accumulation, namely H+ and Pi.•Multifaceted and synergistic effects of H+ and Pi markedly impair muscle contraction.•Fatigue has a bioenergetic basis determined by the rate and extent of metabolite accumulation. 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 (Pi) 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 Pi or H+ directly inhibits force and power of the cross-bridge and decreases myofibrillar Ca2+ sensitivity, whereas Pi 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.