Calcium signaling in insulin action on striated muscle

• Insulin induces [Ca2+]i transients in skeletal and cardiac muscle cells.
• Contribution of insulin-induced [Ca2+]i transients to GLUT4 translocation in skeletal muscle cells.
• Contribution of insulin-induced [Ca2+]i transients to GLUT4 translocation in cardiomyocytes.
• SER–mitochondria interactions in skeletal muscle cells.
• Possible mechanisms of action of insulin-triggered Ca2+ signaling on GLUT4 translocation and beyond.

Striated muscles (skeletal and cardiac) are major physiological targets of insulin and this hormone triggers complex signaling pathways regulating cell growth and energy metabolism. Insulin increases glucose uptake into muscle cells by stimulating glucose transporter (GLUT4) translocation from intracellular compartments to the cell surface. The canonical insulin-triggered signaling cascade controlling this process is constituted by well-mapped tyrosine, lipid and serine/threonine phosphorylation reactions. In parallel to these signals, recent findings reveal insulin-dependent Ca2+ mobilization in skeletal muscle cells and cardiomyocytes. Specifically, insulin activates the sarco-endoplasmic reticulum (SER) channels that release Ca2+ into the cytosol i.e., the Ryanodine Receptor (RyR) and the inositol 1,4,5-triphosphate receptor (IP3R). In skeletal muscle cells, a rapid, insulin-triggered Ca2+ release occurs through RyR, that is brought about upon S-glutathionylation of cysteine residues in the channel by reactive oxygen species (ROS) produced by the early activation of the NADPH oxidase (NOX2). In cardiomyocytes insulin induces a fast and transient increase in cytoplasmic [Ca2+]i trough L-type Ca2+ channels activation. In both cell types, a relatively slower Ca2+ release also occurs through IP3R activation, and is required for GLUT4 translocation and glucose uptake. The insulin-dependent Ca2+ released from IP3R of skeletal muscle also promotes mitochondrial Ca2+ uptake. We review here these actions of insulin on intracellular Ca2+ channel activation and their impact on GLUT4 traffic in muscle cells, as well as other implications of insulin-dependent Ca2+ release from the SER.

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