Duchenne muscular dystrophy (DMD) is a fatal disease that results from the progressive degeneration of all striated muscle types. Glucocorticoids are currently the only standard-of-care treatment for DMD, but have only mild clinical benefits, a limited treatment window, and many serious side-effects. We have recently demonstrated dramatic efficacy on all striated muscle types in a DMD mouse model resulting from treatment with 2 FDA approved drugs, lisinopril and spironolactone. Early treatment of dystrophic mice with the combination of these drugs, known to have profound clinical value for end-stage heart failure, resulted in significant robust improvements in function and pathology in limb skeletal muscle, diaphragm, and heart. Lisinopril/spironolactone have a long history of safety and efficacy in pediatric cardiomyopathy populations, with almost no side effects, but their benefit in skeletal muscles has not previously been studied. Since glucocorticoids target glucocorticoid steroid hormone receptors, and spironolactone targets the mineralocorticoid steroid hormone receptors, optimized pharmacological modulation of steroid receptors may provide a greatly improved treatment option for DMD patients. In this proposal, we will address the critical preclinical issues for a steroid receptor based treatment approach that will be required to achieve the best possible clinical outcomes. We will identify the optimal therapeutic combination of glucocorticoid and mineralocorticoid receptor modulation and dissect the systemic and physiological mechanisms that result from the optimal steroid receptor based treatment strategy. We will also dissect the molecular mechanisms that underlie the therapeutic effects from the optimal steroid receptor treatment. This information will be required to ultimatel monitor clinical efficacy, identify responders from non-responders, test shelved steroid receptor drugs for improved efficacy or drug repurposing, and identify novel molecular treatment targets. In the proposed studies, we will also determine whether functional and histological improvements from the optimal steroid receptor drug treatment are long lasting and maintain efficacy after exercise and stress. Throughout all proposed experiments, we will conduct comprehensive functional and histological analyses in parallel on diaphragm and limb skeletal muscles and on the heart, since all striated muscles types must be improved for optimal efficacy in patients. These preclinical studies are crucial for identifying parallel therapeutic effects and mechanisms on diaphragm, limb muscles, and heart and will be required to ultimately optimize the clinical potential of steroid receptor drugs in the DMD patient population. Completion of the proposed preclinical studies will likely directly impact the near-term treatment options for patients with DMD.