Journal article
Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart
Proceedings of the National Academy of Sciences of the United States of America, Vol.111(28), pp.E2905-E2914
2014
Abstract
Duchenne muscular dystrophy is a fatal X-linked disease characterized by the absence of dystrophin. Approximately 20% of boys will die of dilated cardiomyopathy that is associated with cytoskeletal protein disarray, contractile dysfunction, and reduced energy production. However, the mechanisms for altered energy metabolism are not yet fully clarified. Calcium influx through the L-type Ca2+ channel is critical for maintaining cardiac excitation and contraction. The L-type Ca2+ channel also regulates mitochondrial function and metabolic activity via transmission of movement of the auxiliary beta subunit through intermediate filament proteins. Here, we find that activation of the L-type Ca2+ channel is unable to induce increases in mitochondrial membrane potential and metabolic activity in intact cardiac myocytes from the murine model of Duchenne muscular dystrophy (mdx) despite robust increases recorded in wt myocytes. Treatment of mdx mice with morpholino oligomers to induce exon skipping of dystrophin exon 23 (that results in functional dystrophin accumulation) or application of a peptide that resulted in block of voltage-dependent anion channel (VDAC) “rescued” mitochondrial membrane potential and metabolic activity in mdx myocytes. The mitochondrial VDAC coimmunoprecipitated with the L-type Ca2+ channel. We conclude that the absence of dystrophin in the mdx ventricular myocyte leads to impaired functional communication between the L-type Ca2+ channel and mitochondrial VDAC. This appears to contribute to metabolic inhibition. These findings provide new mechanistic and functional insight into cardiomyopathy associated with Duchenne muscular dystrophy.
Details
- Title
- Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart
- Authors/Creators
- H.M. Viola (Author/Creator) - The University of Western AustraliaA.M. Adams (Author/Creator) - Perron Institute for Neurological and Translational ScienceS.M.K. Davies (Author/Creator) - Harry Perkins Institute of Medical ResearchS. Fletcher (Author/Creator) - The University of Western AustraliaA. Filipovska (Author/Creator) - Harry Perkins Institute of Medical ResearchL.C. Hool (Author/Creator) - Victor Chang Cardiac Research Institute
- Publication Details
- Proceedings of the National Academy of Sciences of the United States of America, Vol.111(28), pp.E2905-E2914
- Publisher
- National Academy of Sciences
- Identifiers
- 991005541168307891
- Copyright
- © 2014 National Academy of Sciences
- Murdoch Affiliation
- Centre for Comparative Genomics
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Cardiac & Cardiovascular Systems
- ESI research areas
- Molecular Biology & Genetics