Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate

•rAAV vectors increase cardiac-specific expression of RNR and elevate cardiomyocyte 2-dATP levels.•Elevated myocardial RNR and subsequent increase in 2-dATP rescues the performance of failing myocardium, an effect that persists long term.•We show the ability to increase both cardiac baseline function and high workload contractile performance in aged (22- to 24-month old) mdx4cv mice, by high-level muscle-specific expression of either microdystrophin or RNR.•Five months post-treatment, mice systemically injected with rAAV6 vector carrying a striated muscle-specific regulatory cassette driving expression of microdystrophin in both skeletal and cardiac muscle, exhibited the greatest effect on systolic function. In comparison, mice treated with rAAV6 vector carrying RNR that expresses exclusively in cardiac muscle not only exhibited greatly improved baseline systolic function but also improved diastolic function.•Importantly, vector-directed overexpression of RNR did not impair cardiac reserve during increased physiological demand in aged mdx4cv hearts.