title: Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.
abstract: Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD.
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio; and.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Chadwick
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio; and.|Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Sayak
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio; and.
authors.forename: Jeovanna
authors.initials: J
authors.lastname: Lowe
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio; and.|Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio; and rafael-fortney.1@osu.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D017706:Lisinopril / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D009124:Muscle Proteins / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013148:Spironolactone / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D009124:Muscle Proteins; D013148:Spironolactone; D017706:Lisinopril
keywords: Duchenne muscular dystrophy; eplerenone; microarray; mineralocorticoid receptor; sarcolemma; spironolactone