Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.
Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor.



The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril.



Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls.In vivomeasurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm,extensor digitorum longus, and cardiac papillary muscle force was measuredex vivo, followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles.



Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment.



These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Jeovanna
J
Lowe
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Kyle T
KT
Floyd
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Neha
N
Rastogi
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Eric J
EJ
Schultz
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Jessica A
JA
Chadwick
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Sarah A
SA
Swager
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Jonathan G
JG
Zins
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Feni K
FK
Kadakia
Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA.
Suzanne
S
Smart
Dept. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Elise P
EP
Gomez-Sanchez
Dept. of Internal Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Celso E
CE
Gomez-Sanchez
Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA.
Subha V
SV
Raman
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Paul M L
PM
Janssen
Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
Jill A
JA
Rafael-Fortney
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D000077545:Eplerenone; D055785:Gene Knockdown Techniques; D006321:Heart / Q000187:drug effects*; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016896:Treatment Outcome; D049411:Utrophin / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; C483600:Utrn protein, mouse; D049411:Utrophin; D013148:Spironolactone; D000077545:Eplerenone; D017706:Lisinopril
Duchenne muscular dystrophy; eplerenone; lisinopril; mineralocorticoid receptors; spironolactone