Ca(2+) permeation and/or binding to Ca(V)1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function

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.