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

Helena M Viola; Victoria P A Johnstone; Henrietta Cserne Szappanos; Tara R Richman; Tatiana Tsoutsman; Aleksandra Filipovska; Christopher Semsarian; Jonathan G Seidman; Christine E Seidman; Livia C Hool

doi:10.1016/j.jacbts.2015.12.001

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

JACC Basic Transl Sci. 2016 Feb 13;1(1-2):61-72. doi: 10.1016/j.jacbts.2015.12.001. eCollection 2016 Jan-Feb.

Authors

Affiliations

¹ School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Australia.
² The Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, Australia.
³ Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.
⁴ Sydney Medical School, University of Sydney, Australia.
⁵ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
⁶ Harvard Medical School, Harvard University, Boston, Massachusetts.
⁷ Victor Chang Cardiac Research Institute, Sydney, Australia.

Abstract

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.

Keywords: HCM, hypertrophic cardiomyopathy; ICa-L, L-type Ca2+ channel; L-type calcium channel; MHC, myosin heavy chain; VDAC, voltage-dependent anion channel; [Ca2+]i, intracellular calcium; calcium; cardiomyopathy; mitochondria; Ψm, mitochondrial membrane potential.

Publication types

Review