Journal
SKELETAL MUSCLE
Volume 5, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13395-014-0027-1
Keywords
Ca(V)1.1; CaM kinase II; Fatigue; Fiber type; Protein synthesis and Skeletal muscle
Categories
Funding
- Muscular Dystrophy Association
- NIH [AR053349, AR041802, AR060831, T32 HL007676]
- Mexican Council of Science and Technology [186607]
- Swedish Research Council
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Background: Ca2+ influx through Ca(V)1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca2+ 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 Ca2+ binding and/or permeation defect in the voltage-dependent Ca2+ channel, Ca(V)1.1, and used Ca2+ imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca2+ imaging techniques to define pathways modulated by Ca2+ 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 Ca2+ binding and/or permeation (E1014K, EK), we demonstrate that Ca(V)1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca2+ stores during sustained activity. Decreases in these Ca2+-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 Ca2+ 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, Ca2+ binding and/or permeation via the Ca(V)1.1 pore plays an important modulatory role in muscle performance.
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