Viola 2016 JACC: Basic to Translational Science

Viola HM, Johnstone VPA, Szappanos HC, Richman TR, Tsoutsman T, Filipovska A, Semsarian C, Seidman JG, Seidman CE, Hool LC (2016) The role of the L-type Ca2+ channel in altered metabolic activity in a murine model of hypertrophic cardiomyopathy. JACC: Basic to Translational Science 1: 61–72.

» PMID: 30167506 Open Access

Viola HM, Johnstone VPA, Szappanos HC, Richman TR, Tsoutsman T, Filipovska A, Semsarian C, Seidman JG, Seidman CE, Hool LC (2016) JACC Basic Transl Sci

Abstract: Highlights

Heterozygous mice (αMHC^403/+) 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 (I_Ca-L) in regulating mitochondrial function in Arg403Gln (αMHC^403/+) mice. Activation of I_Ca-L in αMHC^403/+ 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 I_Ca-L antagonists and when F-actin or β-tubulin were depolymerized. I_Ca-L antagonists may be effective in reducing the cardiomyopathy in HCM by altering metabolic activity.

Summary

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: Calcium, Cardiomyopathy, L-type calcium channel, Mitochondria

• O2k-Network Lab: AU Perth Filipovska A

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Myopathy 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 

Coupling state: OXPHOS  Pathway: N, S, CIV  HRR: Oxygraph-2k 

2016-05