Increased Excitability of Acidified Skeletal Muscle: Role of Chloride Conductance

Generation of the action potentials (AP) necessary to activate skeletal muscle fibers requires that inward membrane currents exceed outward currents and thereby depolarize the fibers to the voltage threshold for AP generation. Excitability therefore depends on both excitatory Na(+) currents and inhibitory K(+) and Cl(−) currents. During intensive exercise, active muscle loses K(+) and extracellular K(+) ([K(+)](o)) increases. Since high [K(+)](o) leads to depolarization and ensuing inactivation of voltage-gated Na(+) channels and loss of excitability in isolated muscles, exercise-induced loss of K(+) is likely to reduce muscle excitability and thereby contribute to muscle fatigue in vivo. Intensive exercise, however, also leads to muscle acidification, which recently was shown to recover excitability in isolated K(+)-depressed muscles of the rat. Here we show that in rat soleus muscles at 11 mM K(+), the almost complete recovery of compound action potentials and force with muscle acidification (CO(2) changed from 5 to 24%) was associated with reduced chloride conductance (1731 ± 151 to 938 ± 64 μS/cm(2), P < 0.01) but not with changes in potassium conductance (405 ± 20 to 455 ± 30 μS/cm(2), P < 0.16). Furthermore, acidification reduced the rheobase current by 26% at 4 mM K(+) and increased the number of excitable fibers at elevated [K(+)](o). At 11 mM K(+) and normal pH, a recovery of excitability and force similar to the observations with muscle acidification could be induced by reducing extracellular Cl(−) or by blocking the major muscle Cl(−) channel, ClC-1, with 30 μM 9-AC. It is concluded that recovery of excitability in K(+)-depressed muscles induced by muscle acidification is related to reduction in the inhibitory Cl(−) currents, possibly through inhibition of ClC-1 channels, and acidosis thereby reduces the Na(+) current needed to generate and propagate an AP. Thus short term regulation of Cl(−) channels is important for maintenance of excitability in working muscle.