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- Title
Ca<sup>2+</sup> permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca<sup>2+</sup> signaling to sustain muscle function.
- Authors
Chang Seok Lee; Dagnino-Acosta, Adan; Yarotskyy, Viktor; Hanna, Amy; Lyfenko, Alla; Knoblauch, Mark; Georgiou, Dimitra K.; Poché, Ross A.; Swank, Michael W.; Cheng Long; Ismailov, Iskander I.; Lanner, Johanna; Tran, Ted; KeKe Dong; Rodney, George G.; Dickinson, Mary E.; Beeton, Christine; Pumin Zhang; Dirksen, Robert T.; Hamilton, Susan L.
- Abstract
Background: Ca2+ influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca2+ permeation through CaV1.1 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 permeation defect in the voltage-dependent Ca2+ channel, CaV1.1, 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 permeation of CaV1.1. 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 CaV1.1 required for Ca2+ binding and permeation (E1014K, EK), we demonstrate that CaV1.1 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 Ca2+ binding defect in CaV1.1 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 CaV1.1 pore plays an important modulatory role in muscle performance.
- Subjects
SKELETAL muscle; MUSCLE contraction; CALCIUM; WESTERN immunoblotting; IMMUNOHISTOCHEMISTRY; PROTEIN synthesis
- Publication
Skeletal Muscle, 2015, Vol 5, Issue 1, p53
- ISSN
2044-5040
- Publication type
Article
- DOI
10.1186/s13395-014-0027-1