Aims: Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy (DMD), a disease caused by lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying disease progression are unclear and treatments limited. Here, we tested the hypothesis of a greater susceptibility to opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic (mdx mice) (prior to development of overt cardiomyopathy) when subjected to a stress protocol, and determined whether prevention of PTP opening is involved in the cardio protective effect of sildenafil, which we have previously reported in mdx mice. Methods and results: Using the [(3)H]-DOG method to quantify PTP opening in ex vivo perfused hearts, we demonstrate that, compared to controls, hearts from young mdx mice subjected to ischemia-reperfusion (I-R) display excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from non-ischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and ROS handling, but enhanced Ca2+ uptake velocity, and premature opening of the PTP, which may predispose to I-R-induced injury. Administration of a single dose of sildenafil to mdx mice, prior to I-R prevented excessive PTP opening and its downstream consequences, and reduced tissue Ca(2+) levels. Furthermore, mitochondrial Ca(2+) uptake velocity was reduced following sildenafil treatment. Conclusion: Beyond documenting that an increased susceptibility to opening of the mitochondrial PTP in mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations, and is reported safe and well-tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca(2+) loading, and mitochondrial Ca(2+) uptake.

Related posts:

1. Ca2+ overload and mitochondrial permeability transition pore activation in living {delta}-sarcoglycan deficient cardiomyocytes.
2. Mitochondrial Ca(2+) transport and permeability transition in zebrafish (Danio rerio).
3. Myocardial fibrosis is unaltered by long-term administration of L-arginine in dystrophin deficient mdx mice: A histomorphometric analysis.
4. Proteomic Profiling of the Dystrophin-Deficient MDX Heart Reveals Drastically Altered Levels of Key Metabolic and Contractile Proteins.
5. Extracellular Signal-Regulated Kinase-2 within the Ventral Tegmental Area Regulates Responses to Stress.

Tags: Muscular Dystrophy

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