Abstract
High amplitude depolarizations of skeletal muscle fibers induce massive SR Ca2+ release that progressively declines with time and completely annihilates if depolarization is maintained during several tens of seconds. Several processes may be involved in the decline of SR Ca2+ release: cytosolic Ca2+-dependent closure of SR Ca2+ release channels, voltage-dependent inactivation of SR Ca2+ release channels and SR Ca2+ depletion. This study aimed to determine how these processes are involved during long-lasting depolarizations of isolated mouse muscle fibers under voltage control by measuring cytosolic Ca2+ changes using fura-2 or luminal SR Ca2+ changes using fluo5N in the presence of 50 mM internal EGTA. Decays of cytosolic Ca2+ signals elicited by 50-s duration depolarizations became more marked and faster with depolarization amplitude. Pre-depolarizations of 2-min duration and of increasing amplitude induced a reduction of voltage-activated cytosolic Ca2+ signals with a mean voltage of −50 mV inducing half-maximum reduction. A comparable protocol applied to fibers loaded with fluo5N showed that low voltage depolarizing prepulses induced a marked SR Ca2+ depletion that contributed to reduce a subsequent voltage-activated SR Ca2+ change with a mean voltage of −50 mV inducing half-maximum reduction. Measuring SR Ca2+ changes in response to long-lasting depolarizations indicated that SR Ca2+ release channels inactivated in response to much higher depolarizations with a mean half-maximum inactivation voltage of −20 mV. Finally, trains of action potential of 50 s duration produced cytosolic Ca2+ signals that decayed with time, whereas SR Ca2+ changes did not display any sign of inactivation. These results indicate that the decline in SR Ca2+ release during long-lasting depolarizations mainly results from SR Ca2+ depletion. The work was supported by AFM, CNRS and University Lyon 1.
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