The Role of the L-Type Ca Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy.

Heterozygous mice ( ) expressing the human disease-causing mutation exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of mice with the L-type calcium channel (I) antagonist diltiazem has been shown to decrease left ventricular anterior wall thickness, cardiac myocyte hypertrophy, disarray, and fibrosis. However, the role of the I in the development of HCM is not known. In addition to maintaining cardiac excitation and contraction in myocytes, the I also regulates mitochondrial function through transmission of movement of I via cytoskeletal proteins to mitochondrial voltage-dependent anion channel. Here, the authors investigated the role of I in regulating mitochondrial function in mice. Whole-cell patch clamp studies showed that I current inactivation kinetics were significantly increased in cardiac myocytes, but that current density and channel expression were similar to wild-type cardiac myocytes. Activation of I caused a significantly greater increase in mitochondrial membrane potential and metabolic activity in . These increases were attenuated with I antagonists and following F-actin or β-tubulin depolymerization. The authors observed increased levels of fibroblast growth factor-21 in  mice, and altered mitochondrial DNA copy number consistent with altered mitochondrial activity and the development of cardiomyopathy. These studies suggest that the mutation leads to altered functional communication between I and mitochondria that is associated with increased metabolic activity, which may contribute to the development of cardiomyopathy. I antagonists may be effective in reducing the cardiomyopathy in HCM by altering metabolic activity.