The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy.
Heterozygous mice (αMHC ) 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 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 αMHC mice. Whole-cell patch clamp studies showed that ICa-L current inactivation kinetics were significantly increased in αMHC 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 αMHC . 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 αMHC 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.
['Viola|Helena M|HM|', 'Johnstone|Victoria P A|VPA|', 'Cserne Szappanos|Henrietta|H|', 'Richman|Tara R|TR|', 'Tsoutsman|Tatiana|T|', 'Filipovska|Aleksandra|A|', 'Semsarian|Christopher|C|', 'Seidman|Jonathan G|JG|', 'Seidman|Christine E|CE|', 'Hool|Livia C|LC|']
cardiomyopathy L-type calcium channel calcium mitochondria HCM, hypertrophic cardiomyopathy ICa-L, L-type Ca2+ channel MHC, myosin heavy chain VDAC, voltage-dependent anion channel [Ca2+]i, intracellular calcium Ψm, mitochondrial membrane potential