Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury

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PROJECT SUMMARY Mineralocorticoid receptor antagonists are FDA-approved drugs that have a long history of safety and efficacy for treating heart failure. These drugs block activation of mineralocorticoid receptors (MR) by the endogenous mineralocorticoid aldosterone and prevent these steroid hormone receptors from translocating to the nucleus and regulating gene transcription. Chronic overactivation of MR by the natural hormone aldosterone is known to exacerbate cell damage in cardiovascular diseases. We have repeatedly demonstrated that treatment with a MR antagonist plus an angiotensin converting enzyme inhibitor, which acts upstream to inhibit aldosterone production, have therapeutic benefits on both heart and skeletal muscles in mouse models of Duchenne muscular dystrophy. The observed preclinical efficacy of MR antagonists on dystrophic skeletal muscle function and pathology was a surprise, given that MR had never been identified in skeletal muscles. We have now demonstrated that MR are present in skeletal muscles and function in gene expression. We have also shown that MR antagonists prevent ongoing dystrophic muscle damage, supporting these drugs act at an early stage of the pathogenic process. Inflammatory cells present in damaged muscles contain high levels of the enzyme required for aldosterone synthesis and increased levels of aldosterone may contribute to chronic muscle damage in muscular dystrophy. Efficacy of drugs that prevent activation of MR in muscular dystrophy models and the presence of local aldosterone production during chronic and acute skeletal muscle injuries support the scientific premise that MR may be a therapeutic target for chronic skeletal muscle diseases and acute injuries. However, the role of mineralocorticoid receptors in normal skeletal muscle function and pathogenesis is not known. In this application, we will use a genetic approach to dissect MR functions and downstream molecular mechanisms in acute and chronic muscle injuries. Information about the role of these receptors in skeletal muscle will provide the basis for modulating MR as a therapeutic target for a wide variety of muscle pathologies.