The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy
Heterozygous mice (αMHC403/+) expressing the human disease-causing mutation Arg403Gln exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of αMHC403/+mice with the L-type calcium channel (ICa-L) antagoni...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | JACC: Basic to Translational Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452302X16000115 |
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| author | Helena M. Viola, PhD Victoria P.A. Johnstone, PhD Henrietta Cserne Szappanos, PhD Tara R. Richman, PhD Tatiana Tsoutsman, PhD Aleksandra Filipovska, PhD Christopher Semsarian, MD, PhD Jonathan G. Seidman, PhD Christine E. Seidman, MD, PhD Livia C. Hool, PhD |
| author_facet | Helena M. Viola, PhD Victoria P.A. Johnstone, PhD Henrietta Cserne Szappanos, PhD Tara R. Richman, PhD Tatiana Tsoutsman, PhD Aleksandra Filipovska, PhD Christopher Semsarian, MD, PhD Jonathan G. Seidman, PhD Christine E. Seidman, MD, PhD Livia C. Hool, PhD |
| author_sort | Helena M. Viola, PhD |
| collection | DOAJ |
| description | Heterozygous mice (αMHC403/+) expressing the human disease-causing mutation Arg403Gln exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of αMHC403/+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 αMHC403/+mice. Whole-cell patch clamp studies showed that ICa-L current inactivation kinetics were significantly increased in αMHC403/+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 αMHC403/+. 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 αMHC403/+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. |
| first_indexed | 2024-12-11T06:07:27Z |
| format | Article |
| id | doaj.art-efa6bc8070ff4490b1a1f568bb63aec1 |
| institution | Directory Open Access Journal |
| issn | 2452-302X |
| language | English |
| last_indexed | 2024-12-11T06:07:27Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
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| series | JACC: Basic to Translational Science |
| spelling | doaj.art-efa6bc8070ff4490b1a1f568bb63aec12022-12-22T01:18:16ZengElsevierJACC: Basic to Translational Science2452-302X2016-01-0111617210.1016/j.jacbts.2015.12.001The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic CardiomyopathyHelena M. Viola, PhD0Victoria P.A. Johnstone, PhD1Henrietta Cserne Szappanos, PhD2Tara R. Richman, PhD3Tatiana Tsoutsman, PhD4Aleksandra Filipovska, PhD5Christopher Semsarian, MD, PhD6Jonathan G. Seidman, PhD7Christine E. Seidman, MD, PhD8Livia C. Hool, PhD9School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, AustraliaSchool of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, AustraliaSchool of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, AustraliaThe Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, AustraliaAgnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, AustraliaThe Harry Perkins Institute for Medical Research, The University of Western Australia, Crawley, AustraliaAgnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, AustraliaHarvard Medical School, Harvard University, Boston, MassachusettsHarvard Medical School, Harvard University, Boston, MassachusettsSchool of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, AustraliaHeterozygous mice (αMHC403/+) expressing the human disease-causing mutation Arg403Gln exhibit cardinal features of hypertrophic cardiomyopathy (HCM) including hypertrophy, myocyte disarray, and increased myocardial fibrosis. Treatment of αMHC403/+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 αMHC403/+mice. Whole-cell patch clamp studies showed that ICa-L current inactivation kinetics were significantly increased in αMHC403/+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 αMHC403/+. 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 αMHC403/+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.http://www.sciencedirect.com/science/article/pii/S2452302X16000115calciumcardiomyopathyL-type calcium channelmitochondria |
| spellingShingle | Helena M. Viola, PhD Victoria P.A. Johnstone, PhD Henrietta Cserne Szappanos, PhD Tara R. Richman, PhD Tatiana Tsoutsman, PhD Aleksandra Filipovska, PhD Christopher Semsarian, MD, PhD Jonathan G. Seidman, PhD Christine E. Seidman, MD, PhD Livia C. Hool, PhD The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy JACC: Basic to Translational Science calcium cardiomyopathy L-type calcium channel mitochondria |
| title | The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy |
| title_full | The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy |
| title_fullStr | The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy |
| title_full_unstemmed | The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy |
| title_short | The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy |
| title_sort | role of the l type ca2 channel in altered metabolic activity in a murine model of hypertrophic cardiomyopathy |
| topic | calcium cardiomyopathy L-type calcium channel mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S2452302X16000115 |
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