Abstract
BackgroundCa2+ 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.MethodsWe generated a mouse with a Ca2+ binding and/or 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/or permeation of CaV1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles.ResultsUsing mice with a pore mutation in CaV1.1 required for Ca2+ binding and/or 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/or Ca2+ binding defect in CaV1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers.ConclusionsWhile not essential for excitation-contraction coupling, Ca2+ binding and/or permeation via the CaV1.1 pore plays an important modulatory role in muscle performance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-014-0027-1) contains supplementary material, which is available to authorized users.
Highlights
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
To directly delineate the role of Ca2+ permeation through CaV1.1 in skeletal muscle function, we created a mouse with a Ca2+ binding and permeation defect in CaV1.1. We demonstrate that this CaV1.1-mediated pathway utilizes the flexibility of Ca2+ signaling to regulate calmodulin-dependent protein kinase II (CaMKII) and calcineurin activation, thereby enhancing sarcoplasmic reticulum (SR) Ca2+ store refilling and protein synthesis to modulate fatigue susceptibility, muscle size, and fiber type distribution
To identify upstream events that regulate protein synthesis, we examined the levels of p-S473-Akt/Akt [40], pT308-Akt/Akt, and pT202/Y204-ERK1/2 and found that all of these phosphorylation events were decreased in both the soleus and extensor digitorum longus (EDL) of EK mice treated with insulin compared to the
Summary
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. Excitation-contraction coupling (ECC) in skeletal muscle involves a mechanical interaction between the L-type voltage-dependent Ca2+ channel (CaV1.1) and the sarcoplasmic reticulum (SR) Ca2+ release channel (the ryanodine receptor, RyR1). Ca2+ entry through CaV1.1 is not required for skeletal muscle ECC [1], CaV1.1 opens after the initial voltage-gated release event to allow Ca2+ to both bind and permeate the channel pore [2]. There is only limited understanding of the role of Ca2+ permeation via CaV1.1, this influx has been suggested to regulate clustering of nicotinic acetylcholine receptors at the neuromuscular junction [7,8,9] and muscle plasticity [10].
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