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

JACC. Basic to Translational Science
Helena M ViolaLivia C Hool

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 (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 403/+ mice. Whole-cell patch clamp studies showed that ICa-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 ICa-L caused a significantly greater increase in mitochondrial membrane potential and metabolic activity in αMHC 403/+ . These increases we...Continue Reading

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Citations

Aug 22, 2020·The Journal of Physiology·Tanya SolomonHelena Viola
Aug 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Helena M ViolaLivia C Hool
Jul 21, 2016·Channels·Helena M Viola, Livia C Hool
Aug 25, 2017·Science Advances·Kara L PerksAleksandra Filipovska
Jan 11, 2020·European Journal of Heart Failure·C Vaughan TuohyStephen B Heitner
Sep 17, 2021·Circulation Research·Shuhong MaFeng Lan

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Methods Mentioned

BETA
transmission electron microscopy

Software Mentioned

GraphPad Prism
GraphPad

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