title: Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy.
abstract: 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.
authors: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors: Jessica A
authors: JA
authors: Chadwick
authors: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors: Sarah A
authors: SA
authors: Swager
authors: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors: Jeovanna
authors: J
authors: Lowe
authors: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.
authors: Steven S
authors: SS
authors: Welc
authors: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.
authors: James G
authors: JG
authors: Tidball
authors: Department of Internal Medicine.
authors: Celso E
authors: CE
authors: Gomez-Sanchez
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Elise P
authors: EP
authors: Gomez-Sanchez
authors: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors: Jill A
authors: JA
authors: Rafael-Fortney
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000235:genetics; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D019405:Cytochrome P-450 CYP11B2