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

项目总结 盐皮质激素受体拮抗剂是FDA批准的药物，具有长期的安全性和 治疗心力衰竭的疗效。这些药物通过以下途径阻断盐皮质激素受体(MR)的激活 内源性盐皮质激素醛固酮和阻止这些类固醇激素受体 移位到细胞核，调节基因转录。慢性过度激活的MR 众所周知，天然激素醛固酮会加剧心血管疾病中的细胞损伤。我们有 反复证明使用MR拮抗剂加血管紧张素转换酶治疗 上游抑制醛固酮生成的抑制剂对两个心脏都有治疗作用 以及Duchenne肌营养不良症小鼠模型中的骨骼肌。观察到的临床前 MR拮抗剂对营养不良骨骼肌功能和病理的疗效令人惊讶，给出了 从未在骨骼肌中发现过MR。我们现在已经证明了Mr是 存在于骨骼肌中，并在基因表达中发挥作用。我们也已经证明了对抗性先生 预防持续的营养不良肌肉损伤，支持这些药物在早期阶段发挥作用 致病过程。受损肌肉中的炎性细胞含有高水平的这种酶 合成所需的醛固酮和升高的醛固酮水平可能导致慢性 肌营养不良症中的肌肉损伤。防止肌肉中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 肌肉损伤支持了MR可能是慢性骨骼疾病治疗靶点的科学假设 肌肉疾病和急性损伤。然而，盐皮质激素受体在正常骨骼中的作用 肌肉功能和发病机制尚不清楚。在本应用程序中，我们将使用遗传方法来 剖析MR在急慢性肌肉损伤中的功能及其下游分子机制。 有关这些受体在骨骼肌中作用的信息将为调节MR提供基础。 作为治疗多种肌肉病变的靶点。

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.