Heterozygous mice (αMHC403/+ ) expressing the human disease-causing mutation Arg403Gln exhibit cardinal features of hypertrophic
cardiomyopathy (HCM) including
hypertrophy, myocyte disarray, and increased myocardial
fibrosis. Treatment of αMHC403/+ mice with the
L-type calcium channel (ICa-L) antagonist
diltiazem has been shown to decrease left ventricular anterior wall thickness, cardiac myocyte
hypertrophy, disarray, and
fibrosis. However, the role of the ICa-L in the development of HCM is not known. In addition to maintaining cardiac excitation and contraction in myocytes, the ICa-L also regulates mitochondrial function through transmission of movement of ICa-L via
cytoskeletal proteins to mitochondrial
voltage-dependent anion channel. Here, the authors investigated the role of ICa-L in regulating mitochondrial function in αMHC403/+ mice. Whole-cell patch clamp studies showed that ICa-L current inactivation kinetics were significantly increased in αMHC403/+ cardiac myocytes, but that current density and channel expression were similar to wild-type cardiac myocytes. Activation of ICa-L caused a significantly greater increase in mitochondrial membrane potential and metabolic activity in αMHC403/+ . These increases were attenuated with ICa-L antagonists and following
F-actin or β-
tubulin depolymerization. The authors observed increased levels of fibroblast growth factor-21 in αMHC403/+ 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 ICa-L and mitochondria that is associated with increased metabolic activity, which may contribute to the development of
cardiomyopathy. ICa-L antagonists may be effective in reducing the
cardiomyopathy in HCM by altering metabolic activity.