The L-type Ca channel contributes to alterations in mitochondrial calcium

23 24 The L-type Ca channel is the main route for calcium entry into cardiac myocytes 25 and it is essential for contraction. Alterations in whole cell L-type Ca channel 26 current and Ca homeostasis have been implicated in the development of 27 cardiomyopathies. Cytoskeletal proteins can influence whole cell L-type Ca current 28 and mitochondrial function. Duchenne Muscular Dystrophy is a fatal X-linked disease 29 that leads to progressive muscle weakness due to the absence of cytoskeletal 30 protein dystrophin. This includes dilated cardiomyopathy but the mechanisms are not 31 well understood. We sought to identify the effect of alterations in whole cell L-type 32 Ca channel current on mitochondrial function in the murine model of Duchenne 33 Muscular Dystrophy (mdx). Activation of the L-type Ca channel with the 34 dihydropyridine agonist BayK(-) caused a significantly larger increase in cytosolic 35 Ca in mdx versus wt ventricular myocytes. Consistent with elevated cytosolic Ca, 36 resting mitochondrial Ca, NADH and mitochondrial superoxide were significantly 37 greater in mdx versus wt myocytes. Activation of the channel with BayK(-) caused a 38 further increase in mitochondrial Ca, NADH and superoxide in mdx myocytes. The 39 ratios of the increases were similar to the ratios recorded in wt myocytes. In 40 mitochondria isolated from 8 week old mdx hearts respiration and mitochondrial 41 electron transport chain complex activity were similar to mitochondria isolated from 42 wt hearts. We conclude that mitochondria function at a higher resting calcium in the 43 intact mdx myocyte and activation of the L-type Ca channel contributes to 44 alterations in calcium handling by the mitochondria. This perturbation may contribute 45 to the development of cardiomyopathy. 46