| First Author | Viola HM | Year | 2016 |
| Journal | JACC Basic Transl Sci | Volume | 1 |
| Issue | 1-2 | Pages | 61-72 |
| PubMed ID | 30167506 | Mgi Jnum | J:307854 |
| Mgi Id | MGI:6726019 | Doi | 10.1016/j.jacbts.2015.12.001 |
| Citation | Viola HM, et al. (2016) The Role of the L-Type Ca(2+) Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy. JACC Basic Transl Sci 1(1-2):61-72 |
| abstractText | Heterozygous mice (alphaMHC(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 alphaMHC(403/+) 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 alphaMHC(403/+) mice. Whole-cell patch clamp studies showed that ICa-L current inactivation kinetics were significantly increased in alphaMHC(403/+) 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 alphaMHC(403/+) . These increases were attenuated with ICa-L antagonists and following F-actin or beta-tubulin depolymerization. The authors observed increased levels of fibroblast growth factor-21 in alphaMHC(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 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. |
