Abstract
We exploited a variety of mouse models to assess the roles of JP45-CASQ1 (CASQ, calsequestrin) and JP45-CASQ2 on calcium entry in slow twitch muscles. In flexor digitorum brevis (FDB) fibers isolated from JP45-CASQ1-CASQ2 triple KO mice, calcium transients induced by tetanic stimulation rely on calcium entry via La3+- and nifedipine-sensitive calcium channels. The comparison of excitation-coupled calcium entry (ECCE) between FDB fibers from WT, JP45KO, CASQ1KO, CASQ2KO, JP45-CASQ1 double KO, JP45-CASQ2 double KO, and JP45-CASQ1-CASQ2 triple KO shows that ECCE enhancement requires ablation of both CASQs and JP45. Calcium entry activated by ablation of both JP45-CASQ1 and JP45-CASQ2 complexes supports tetanic force development in slow twitch soleus muscles. In addition, we show that CASQs interact with JP45 at Ca2+ concentrations similar to those present in the lumen of the sarcoplasmic reticulum at rest, whereas Ca2+ concentrations similar to those present in the SR lumen after depolarization-induced calcium release cause the dissociation of JP45 from CASQs. Our results show that the complex JP45-CASQs is a negative regulator of ECCE and that tetanic force development in slow twitch muscles is supported by the dynamic interaction between JP45 and CASQs.
Highlights
In a previous study we showed that ablation of JP45 in a CASQ1 KO background causes in flexor digitorum brevis (FDB) fibers a robust excitation-coupled calcium entry (ECCE) via Cav1.1, which supports tetanic calcium transients [12]
The decay of force development in EDL muscles from JP45-CASQ1 double KO mice was partially reversed by stimulation with a train of tetani delivered at 0.27 Hz, a maneuver that activates a strong calcium influx which likely leads to replenishment of the intracellular calcium store (Fig. 1, EDL, middle panel, Last Tetani) [12]
The ability of soleus muscles from JP45-CASQ1 double KO mice to develop and maintain an isometric force during tetanic stimulation could be due to the expression of the CASQ2 isoform in slow twitch muscle fibers in addition to massive calcium entry triggered by the ablation of the JP45-CASQ1 complex
Summary
In a previous study we showed that ablation of JP45 in a CASQ1 KO background causes in flexor digitorum brevis (FDB) fibers a robust excitation-coupled calcium entry (ECCE) via Cav1.1, which supports tetanic calcium transients [12]. In FDB fibers from JP45CASQ2 double KO mice, La3ϩ caused a 20% decrease of the peak tetanic calcium transient when compared with that obtained in the presence of 1.8 mM CaCl2
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