Muscle Performance and Electrically Evoked Ca 2+ Release are Compromised in Calsequestrin-1 Null Mice

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In skeletal muscle the sarcoplasmic reticulum (SR) Ca2+ release channels (i.e., ryanodine receptor; RyR1) are critical determinants of contractile filament activation. Recent evidence suggests that several SR proteins may modulate RyR dependent SR Ca2+ release and thus could alter overall function. Recent attention has been focused on the SR luminal protein calsequestrin (Casq) as a SR Ca2+ buffer as well as its potential role in modulating the RyR1, the DHPR and other sarcolemmal channels. In our current work, we tested the hypothesis that mice null for Casq1 will have functional impairments reflecting the role of Casq1 in fast type skeletal muscle. Here we examined functional measures of overall muscle performance in vivo and of fast muscle in vitro, and identified significant deficits in functional performance that indicate an inability to sustain repetitive contractile activation. We then used measures of voltage dependent SR Ca2+ release and SR Ca2+ release flux in single fast type skeletal muscle fibers. Here we demonstrate a decrease in voltage dependent RyR Ca2+ release with single action potentials and a collapse of the Ca2+ release with repetitive trains of pulses. Finally in single voltage clamped muscle fibers we show that SR Ca2+ release flux as well as total SR Ca2+ release is markedly reduced in the Casq1 null myofibers. The voltage dependence of the Ca2+ release flux was not shifted but showed about 50% decrease in the maximum peak Ca2+ release flux in the Casq1 null fibers when compared to the WT counterpart. Taken together we have revealed that the genetic depletion of Casq1 results in significant deficits in contractile activation consistent with alterations in SR Ca2+ release. Supported by RC2 NR011968, R01-AR055099, and T32- AR007592.