The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy

• Heterozygous mice (αMHC403/+) expressing the human hypertrophic cardiomyopathy (HCM) disease causing mutation Arg403Gln exhibit cardinal features of HCM.
• This study investigated the role of L-type Ca2+ channel (ICa-L) in regulating mitochondrial function in Arg403Gln (αMHC403/+) mice.
• Activation of ICa-L in αMHC403/+mice caused a significantly greater increase in mitochondrial membrane potential and metabolic activity when compared to wild-type mice.
• Increases in mitochondrial membrane potential and metabolic activity were attenuated with ICa-L antagonists and when F-actin or β-tubulin were depolymerized.
• ICa-L antagonists may be effective in reducing the cardiomyopathy in HCM by altering metabolic activity.

SummaryHeterozygous 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.

Visual AbstractFigure optionsDownload high-quality image (390 K)Download as PowerPoint slide