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Background  Ca 2+  influx through Ca V 1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca 2+  permeation through Ca V 1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed.    Methods  We generated a mouse with a Ca 2+  binding and/or permeation defect in the voltage-dependent Ca 2+  channel, Ca V 1.1, and used Ca 2+  imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca 2+  imaging techniques to define pathways modulated by Ca 2+  binding and/or permeation of Ca V 1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles.    Results  Using mice with a pore mutation in Ca V 1.1 required for Ca 2+  binding and/or permeation (E1014K, EK), we demonstrate that Ca V 1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca 2+  stores during sustained activity. Decreases in these Ca 2+ -dependent enzyme activities alter downstream signaling pathways (Ras/Erk/mTORC1) that lead to decreased muscle protein synthesis. The physiological consequences of the permeation and/or Ca 2+  binding defect in Ca V 1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers.    Conclusions  While not essential for excitation-contraction coupling, Ca 2+  binding and/or permeation via the Ca V 1.1 pore plays an important modulatory role in muscle performance.    Electronic supplementary material  The online version of this article (doi:10.1186/s13395-014-0027-1) contains supplementary material, which is available to authorized users.

Ca2+ permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca2+ signaling to sustain muscle function