Cross-bridge mechanisms of skeletal muscle fatigue: Effects of hydrogen ion, inorganic phosphate, and age

Intense muscle contraction induces high rates of glycolysis and ATP hydrolysis with resulting increases in inorganic phosphate (Pi) and H +, factors thought to induce fatigue by interfering with steps in the cross-bridge cycle. Force inhibition is less at physiological temperatures; thus the role of low pH in fatigue has been questioned. Effects of pH 6.2 and collective effects with 30 mM Pi on the pCa-force relationship were assessed in skinned fast and slow rat skeletal muscle fibers at low (15°C) and near-physiological temperatures (30°C). At Ca2+ levels characteristic of fatigue, low pH significantly depressed force at both temperatures and in combination with Pi, depressed myofibrillar Ca2+ sensitivity and peak force to a greater extent than either metabolite alone.;Individual effects of elevating H+ or Pi on velocity and power have been well characterized but collective effects less studied. Thus, the effects of simultaneously elevating H+ and Pi on velocity, power, stiffness, and rate of force development (ktr) were measured. H+ and Pi significantly depressed peak fiber power to a greater extent than either ion alone. Force-stiffness ratios significantly decreased with pH 6.2 + 30 mM Pi in both fiber types, suggesting these ions decreased the number and/or force of the high-force state of the cross-bridge. Taken with the finding that low cell pH prolongs the time in the AM·ADP state, thereby depressing velocity, the evidence suggests that H+ and Pi are significant mediators of skeletal muscle fatigue.;The loss of muscle mass and function with age, or sarcopenia, is a significant public health problem. Sarcopenia is characterized by a loss of power with age, but mechanisms of such decrements or sex-specific effects are unknown. Peak force, ktr, and myofibrillar ATPase (among other parameters) were measured in muscle fibers from the vastus lateralis of young (20-30 yr) and old (>70 yr) men and women. The results demonstrate a sex-specific age effect characterized by less absolute peak force, slower cross-bridge kinetics (i.e. reduced ktr), and reduced efficiency in type I fibers from older women. Thus, age-related changes in cross-bridge function represent a potential mechanism for sarcopenia in older women.