Chadwick Jessica A, Swager Sarah A, Lowe Jeovanna, Welc Steven S, Tidball James G, Gomez-Sanchez Celso E, Gomez-Sanchez Elise P, Rafael-Fortney Jill A
Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.
Hum Mol Genet. 2016 Dec 1;25(23):5167-5177. doi: 10.1093/hmg/ddw331.
FDA-approved mineralocorticoid receptor (MR) antagonists are used to treat heart failure. We have recently demonstrated efficacy of MR antagonists for skeletal muscles in addition to heart in Duchenne muscular dystrophy mouse models and that mineralocorticoid receptors are present and functional in skeletal muscles. The goal of this study was to elucidate the underlying mechanisms of MR antagonist efficacy on dystrophic skeletal muscles. We demonstrate for the first time that infiltrating myeloid cells clustered in damaged areas of dystrophic skeletal muscles have the capacity to produce the natural ligand of MR, aldosterone, which in excess is known to exacerbate tissue damage. Aldosterone synthase protein levels are increased in leukocytes isolated from dystrophic muscles compared with controls and local aldosterone levels in dystrophic skeletal muscles are increased, despite normal circulating levels. All genes encoding enzymes in the pathway for aldosterone synthesis are expressed in muscle-derived leukocytes. 11β-HSD2, the enzyme that inactivates glucocorticoids to increase MR selectivity for aldosterone, is also increased in dystrophic muscle tissues. These results, together with the demonstrated preclinical efficacy of antagonists, suggest MR activation is in excess of physiological need and likely contributes to the pathology of muscular dystrophy. This study provides new mechanistic insight into the known contribution of myeloid cells to muscular dystrophy pathology. This first report of myeloid cells having the capacity to produce aldosterone may have implications for a wide variety of acute injuries and chronic diseases with inflammation where MR antagonists may be therapeutic.
美国食品药品监督管理局（FDA）批准的盐皮质激素受体（MR）拮抗剂用于治疗心力衰竭。我们最近在杜兴氏肌营养不良小鼠模型中证明，MR拮抗剂除了对心脏有效外，对骨骼肌也有效，并且盐皮质激素受体在骨骼肌中存在且具有功能。本研究的目的是阐明MR拮抗剂对营养不良性骨骼肌疗效的潜在机制。我们首次证明，聚集在营养不良性骨骼肌受损区域的浸润性髓样细胞有能力产生MR的天然配体醛固酮，已知醛固酮过量会加剧组织损伤。与对照组相比，从营养不良性肌肉中分离出的白细胞中醛固酮合酶蛋白水平升高，尽管循环水平正常，但营养不良性骨骼肌中的局部醛固酮水平升高。醛固酮合成途径中所有编码酶的基因在肌肉来源的白细胞中均有表达。11β-羟类固醇脱氢酶2（11β-HSD2）可使糖皮质激素失活以增加MR对醛固酮的选择性，在营养不良性肌肉组织中也增加。这些结果，连同拮抗剂已证明的临床前疗效，表明MR激活超过了生理需要，可能导致了肌营养不良的病理过程。本研究为髓样细胞对肌营养不良病理的已知作用提供了新的机制见解。关于髓样细胞有能力产生醛固酮的这一首次报道可能对多种急性损伤和伴有炎症的慢性疾病有影响，在这些疾病中MR拮抗剂可能具有治疗作用。
