Role of Ca2+, membrane excitability, and Ca2+ stores in failing muscle contraction with aging

Excitation-contraction (EC) coupling in a population of skeletal muscle fibers of aged mice becomes dependent on the presence of external Ca2+ ions (Payne, A.M., Zheng, Z., Gonzalez, E., Wang, Z.M., Messi, M.L., Delbono, O., 2004b. External Ca(2+)-dependent excitation – contraction coupling in a population of aging mouse skeletal muscle fibers. J. Physiol. 560, 137–155.). However, the mechanism(s) underlying this process remain unknown. In this work, we examined the role of (1) extracellular Ca2+; (2) voltage-induced influx of external Ca2+ ions; (3) sarcoplasmic reticulum (SR) Ca2+ depletion during repeated contractions; (4) store-operated Ca2+ entry (SOCE); (5) SR ultrastructure; (6) SR subdomain localization of the ryanodine receptor; and (7) sarcolemmal excitability in muscle force decline with aging. These experiments show that external Ca2+, but not Ca2+ influx, is needed to maintain force upon repetitive fiber electrical stimulation. Decline in fiber force is associated with depressed SR Ca2+ release. SR Ca2+ depletion, SOCE, and the putative segregated Ca2+ release store do not play a significant role in external Ca2+-dependent contraction. More importantly, a significant number of action potentials fail in senescent mouse muscle fibers subjected to a stimulation frequency. These results indicate that failure to generate action potentials accounts for decreased intracellular Ca2+ mobilization and tetanic force in aging muscle exposed to a Ca2+-free medium.