American journal of physiology. Heart and circulatory physiology

L-type Ca(2+) channel contributes to alterations in mitochondrial calcium handling in the mdx ventricular myocyte.

PMID 23335798


The L-type Ca(2+) channel is the main route for calcium entry into cardiac myocytes, and it is essential for contraction. Alterations in whole cell L-type Ca(2+) channel current and Ca(2+) homeostasis have been implicated in the development of cardiomyopathies. Cytoskeletal proteins can influence whole cell L-type Ca(2+) current and mitochondrial function. Duchenne muscular dystrophy is a fatal X-linked disease that leads to progressive muscle weakness due to the absence of cytoskeletal protein dystrophin. This includes dilated cardiomyopathy, but the mechanisms are not well understood. We sought to identify the effect of alterations in whole cell L-type Ca(2+) channel current on mitochondrial function in the murine model of Duchenne muscular dystrophy (mdx). Activation of the L-type Ca(2+) channel with the dihydropyridine agonist BayK(-) caused a significantly larger increase in cytosolic Ca(2+) in mdx vs. wild-type (wt) ventricular myocytes. Consistent with elevated cytosolic Ca(2+), resting mitochondrial Ca(2+), NADH, and mitochondrial superoxide were significantly greater in mdx vs. wt myocytes. Activation of the channel with BayK(-) caused a further increase in mitochondrial Ca(2+), NADH, and superoxide in mdx myocytes. The ratios of the increases were similar to the ratios recorded in wt myocytes. In mitochondria isolated from 8-wk-old mdx hearts, respiration and mitochondrial electron transport chain complex activity were similar to mitochondria isolated from wt hearts. We conclude that mitochondria function at a higher level of resting calcium in the intact mdx myocyte and activation of the L-type Ca(2+) channel contributes to alterations in calcium handling by the mitochondria. This perturbation may contribute to the development of cardiomyopathy.

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(S)-(−)-Bay K8644, ≥98% (HPLC), solid