Dystrophin Is Required for the Normal Function of the Cardio-Protective KATP Channel in CardiomyocytesReportar como inadecuado




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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 KATP complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including KATP 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 KATP channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the KATP channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective KATP system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients.



Autor: Laura Graciotti, Jodi Becker, Anna Luisa Granata, Antonio Domenico Procopio, Lino Tessarollo , Gianluca Fulgenzi

Fuente: http://plos.srce.hr/



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