Mice Null for Calsequestrin 1 Exhibit Deficits in Functional Performance and Sarcoplasmic Reticulum Calcium HandlingReport as inadecuate




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In skeletal muscle, the release of calcium Ca2+ by ryanodine sensitive sarcoplasmic reticulum SR Ca2+ release channels i.e., ryanodine receptors; RyR1s is the primary determinant of contractile filament activation. Much attention has been focused on calsequestrin CASQ1 and its role in SR Ca2+ buffering as well as its potential for modulating RyR1, the L-type Ca2+ channel dihydropyridine receptor, DHPR and other sarcolemmal channels through sensing luminal Ca2+. The genetic ablation of CASQ1 expression results in significant alterations in SR Ca2+ content and SR Ca2+ release especially during prolonged activation. While these findings predict a significant loss-of-function phenotype in vivo, little information on functional status of CASQ1 null mice is available. We examined fast muscle in vivo and in vitro and identified significant deficits in functional performance that indicate an inability to sustain contractile activation. In single CASQ1 null skeletal myofibers we demonstrate a decrease in voltage dependent RyR Ca2+ release with single action potentials and a collapse of the Ca2+ release with repetitive trains. Under voltage clamp, SR Ca2+ release flux and total SR Ca2+ release are significantly reduced in CASQ1 null myofibers. The decrease in peak Ca2+ release flux appears to be solely due to elimination of the slowly decaying component of SR Ca2+ release, whereas the rapidly decaying component of SR Ca2+ release is not altered in either amplitude or time course in CASQ1 null fibers. Finally, intra-SR Ca2+ during ligand and voltage activation of RyR1 revealed a significant decrease in the SRCa2+free in intact CASQ1 null fibers and a increase in the release and uptake kinetics consistent with a depletion of intra-SR Ca2+ buffering capacity. Taken together we have revealed that the genetic ablation of CASQ1 expression results in significant functional deficits consistent with a decrease in the slowly decaying component of SR Ca2+ release.



Author: Rotimi O. Olojo, Andrew P. Ziman, Erick O. Hernández-Ochoa, Paul D. Allen, Martin F. Schneider, Christopher W. Ward

Source: http://plos.srce.hr/



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