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.