title: Dystrophin is required for the normal function of the cardio-protective K(ATP) channel in cardiomyocytes.
abstract: Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx), which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC). In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (K(ATP)) complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including K(ATP) ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm) is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of K(ATP) channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the K(ATP) channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective K(ATP) system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients.
authors: Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy.
authors: Laura
authors: L
authors: Graciotti
authors: Jodi
authors: J
authors: Becker
authors: Anna Luisa
authors: AL
authors: Granata
authors: Antonio Domenico
authors: AD
authors: Procopio
authors: Lino
authors: L
authors: Tessarollo
authors: Gianluca
authors: G
authors: Fulgenzi
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D003402:Creatine Kinase / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D000099161:Kcnj11 Channel
chemical_list: D002316:Cardiotonic Agents; D003402:Creatine Kinase; D016189:Dystrophin; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D000099161:Kcnj11 Channel