The Role of the L-Type Ca(2+) Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy

Heterozygous mice (αMHC(403/+)) expressing the human disease-causing mutation Arg403Gln exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of αMHC(403/+)mice with the L-type calcium channel (I(Ca-L)) antagonist diltiazem has been shown to decrease left ventricular anterior wall thickness, cardiac myocyte hypertrophy, disarray, and fibrosis. However, the role of the I(Ca-L) in the development of HCM is not known. In addition to maintaining cardiac excitation and contraction in myocytes, the I(Ca-L) also regulates mitochondrial function through transmission of movement of I(Ca-L) via cytoskeletal proteins to mitochondrial voltage-dependent anion channel. Here, the authors investigated the role of I(Ca-L) in regulating mitochondrial function in αMHC(403/+)mice. Whole-cell patch clamp studies showed that I(Ca-L) current inactivation kinetics were significantly increased in αMHC(403/+)cardiac myocytes, but that current density and channel expression were similar to wild-type cardiac myocytes. Activation of I(Ca-L) caused a significantly greater increase in mitochondrial membrane potential and metabolic activity in αMHC(403/+). These increases were attenuated with I(Ca-L) antagonists and following F-actin or β-tubulin depolymerization. The authors observed increased levels of fibroblast growth factor-21 in αMHC(403/+)mice, and altered mitochondrial DNA copy number consistent with altered mitochondrial activity and the development of cardiomyopathy. These studies suggest that the Arg403Gln mutation leads to altered functional communication between I(Ca-L) and mitochondria that is associated with increased metabolic activity, which may contribute to the development of cardiomyopathy. I(Ca-L) antagonists may be effective in reducing the cardiomyopathy in HCM by altering metabolic activity.