High-frequency fatigue in rat skeletal muscle: role of extracellular ion concentrations.

High-frequency fatigue (HFF), the decline of force during continuous tetanic stimulation (lasting 4-40 s), was studied in isolated bundles of rat skeletal muscle fibers. HFF was slower in slow-twitch soleus fibers than in fast-twitch red or white sternomastoid fibers; denervation accelerated fatigue in soleus. Maximal 200-mmol/L potassium contractures of normal amplitude were induced in fatigued fibers, suggesting that crossbridge cycling and the voltage activation of excitation-contraction coupling could still occur maximally, but that activation by action potentials was impaired. An increase in [Na+]o slowed HFF, while a small increase in [K+]o or reduction in [Cl(-)]o accelerated HFF. Increasing the tetanic stimulation frequency exacerbated fatigue. Recovery from HFF proceeded rapidly since force increased markedly within a few seconds when stimulation ceased. These results support the hypothesis that a redistribution of Na+, K+, and Cl- across the transverse tubular membranes during repeated action potential activity induces fatigue by reducing the amplitude and conduction of action potentials.