Membrane excitability and excitation-contraction uncoupling in muscle fatigue.

High-frequency tetanic stimulation is associated with an increase in extracellular and T-tubular K(+) and changes of Na(+) and Cl(-) concentrations, membrane depolarization as well as inactivation of voltage-gated Na(+) channels. These alterations are expected to lead to fiber inexcitability, which is largely prevented by mechanisms intrinsic or extrinsic to muscle fibers. They act by adapting electrical membrane properties or by accelerating the reconstitution of ionic homeostasis. The high Cl(-) conductance of muscle fibers supports the K(+) conductance in fast and complete repolarization and creates a mechanism for the fast reuptake of K(+), thereby reducing the T-tubular K(+) accumulation. Excitability is increased by a Ca(2+) and proteinkinase C dependent inhibition of the Cl(-) conductance which is efficient especially in the T-tubular system. Several mediators activate the Na(+)/K(+)-ATPase and thus enhance the restoration of ionic homeostasis. Examples are purines (ATP, ADP), calcitonin-gene related peptide and adrenaline. It is also necessary to adapt the strength of the sarcoplasmic Ca(2+) concentration to the requirements of tetanic contractions. An overwhelming Ca(2+) signal leads to enzymatically driven excitation-contraction uncoupling. This process is most likely driven by the Ca(2+) dependent protease μ-calpain and might lead to the long-lasting fatigue observed after excessive physical activity.