Ca2+ Binding/Permeation via Calcium Channel, Cav1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism

Ca2+ permeation and/or binding to the skeletal muscle L-type Ca2+ channel (Ca(V)1.1) facilitates activation of Ca2+ /calmodulin kinase type II (CaMKII) and Ca2+ store refilling to reduce muscle fatigue and atrophy (Lee, C. S., Dagnino-Acosta, A., Yarotskyy, V., Hanna, A., Lyfenko, A., Knoblauch, M., Georgiou, D. K., Poche, R. A., Swank, M. W., Long, C., Ismailov, I. I., Lanner, J., Tran, T., Dong, K., Rodney, G. G., Dickinson, M. E., Beeton, C., Zhang, P., Dirksen, R. T., and Hamilton, S. L. (2015) Skelet. Muscle 5, 4). Mice with a mutation (E1014K) in the Cacna1s (alpha(1) subunit of Ca(V)1.1) gene that abolishes Ca2+ binding within the Ca(V)1.1 pore gain more body weight and fat on a chow diet than control mice, without changes in food intake or activity, suggesting that Ca(V)1.1-mediated CaMKII activation impacts muscle energy expenditure. We delineate a pathway (Ca(v)1.1 -> CaMKII -> NOS) in normal skeletal muscle that regulates the intracellular distribution of the fatty acid transport protein, CD36, altering fatty acid metabolism. The consequences of blocking this pathway are decreased mitochondrial beta-oxidation and decreased energy expenditure. This study delineates a previously uncharacterized Ca(V)1.1-mediated pathway that regulates energy utilization in skeletal muscle.