title: Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart.
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 Ca(2+) channel is critical for maintaining cardiac excitation and contraction. The L-type Ca(2+) 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 Ca(2+) 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 Ca(2+) channel. We conclude that the absence of dystrophin in the mdx ventricular myocyte leads to impaired functional communication between the L-type Ca(2+) 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.
authors: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA 6009, Australia;
authors: Helena M
authors: HM
authors: Viola
authors: Western Australian Neuroscience Research Institute and Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia;
authors: Abbie M
authors: AM
authors: Adams
authors: Harry Perkins Institute for Medical Research, The University of Western Australia, Perth, WA 6000, Australia;
authors: Stefan M K
authors: SM
authors: Davies
authors: Western Australian Neuroscience Research Institute and Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia;Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia; and.
authors: Susan
authors: S
authors: Fletcher
authors: Harry Perkins Institute for Medical Research, The University of Western Australia, Perth, WA 6000, Australia;
authors: Aleksandra
authors: A
authors: Filipovska
authors: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA 6009, Australia;Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia livia.hool@uwa.edu.au.
authors: Livia C
authors: LC
authors: Hool
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D016189:Dystrophin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018101:Mice, Inbred mdx; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000473:pathology; D060172:Morpholinos / Q000235:genetics / Q000494:pharmacology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
chemical_list: D020746:Calcium Channels, L-Type; D016189:Dystrophin; D060172:Morpholinos; D002118:Calcium
keywords: cytoskeleton; ion channels; structure