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

项目摘要 盐皮质激素受体拮抗剂是FDA批准的药物，具有很长的安全性历史， 治疗心力衰竭的功效。这些药物阻断盐皮质激素受体（MR）的激活， 内源性盐皮质激素醛固酮并阻止这些类固醇激素受体 转移到细胞核并调节基因转录。慢性过度激活MR 已知天然激素醛固酮会加剧心血管疾病中的细胞损伤。我们有 反复证明MR拮抗剂加血管紧张素转换酶治疗 抑制剂在上游起作用以抑制醛固酮产生，其对两个心脏都具有治疗益处 和骨骼肌的研究。观察到的临床前 MR拮抗剂对营养不良性骨骼肌功能和病理学的功效是令人惊讶的， MR从未在骨骼肌中被发现。我们现在已经证明MR是 存在于骨骼肌中并在基因表达中起作用。我们还表明，MR拮抗剂 预防持续的营养不良性肌肉损伤，支持这些药物在早期阶段的作用， 致病过程存在于受损肌肉中的炎性细胞含有高水平的酶 所需的醛固酮合成和醛固酮水平的增加可能有助于慢性 肌肉萎缩症的肌肉损伤。预防肌肉中MR激活的药物的疗效 慢性和急性骨骼肌营养不良模型和局部醛固酮产生的存在 肌肉损伤支持MR可能是慢性骨骼肌损伤的治疗靶点的科学前提。 肌肉疾病和急性损伤。然而，盐皮质激素受体在正常骨骼肌中的作用 肌肉功能和发病机制尚不清楚。在本申请中，我们将使用遗传方法来 解剖急性和慢性肌肉损伤中的MR功能和下游分子机制。 关于这些受体在骨骼肌中的作用的信息将为调节MR提供基础 作为多种肌肉病变的治疗靶点。

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.