title: Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target.
abstract: Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-type mice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC50 1.3 nM) or antagonist (spironolactone; IC50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC50 0.1 nM) compared with untreated controls. Genes down-regulated more than 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases.
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Chadwick
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: J Spencer
authors.initials: JS
authors.lastname: Hauck
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Jeovanna
authors.initials: J
authors.lastname: Lowe
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Jeremiah J
authors.initials: JJ
authors.lastname: Shaw
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Elise P
authors.initials: EP
authors.lastname: Gomez-Sanchez
authors.affiliation: *Department of Molecular and Cellular Biochemistry, Department of Physiology and Cell Biology, Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine, The Ohio State University, Columbus, Ohio, USA; and Department of Internal Medicine and Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA rafael-fortney.1@osu.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D006801:Humans; D017706:Lisinopril / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009135:Muscular Diseases / Q000188:drug therapy / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology*
chemical_list: D009124:Muscle Proteins; D044101:Receptors, Melanocortin; D013148:Spironolactone; D000450:Aldosterone; D017706:Lisinopril
keywords: aldosterone; gene expression microarray; muscular dystrophy; spironolactone; steroid hormone receptors