Similar Efficacy from Specific and Non-Specific Mineralocorticoid Receptor Antagonist Treatment of Muscular Dystrophy Mice

Article type: Research Article

Authors: Lowe, Jeovanna^a | Floyd, Kyle T.^a | Rastogi, Neha^a | Schultz, Eric J.^a | Chadwick, Jessica A.^a | Swager, Sarah A.^a | Zins, Jonathan G.^a | Kadakia, Feni K.^a | Smart, Suzanne^b | Gomez-Sanchez, Elise P.^c | Gomez-Sanchez, Celso E.^d | Raman, Subha V.^b | Janssen, Paul M.L.^{a; 1} | Rafael-Fortney, Jill A.^{a; 1; *}

Affiliations: [a] Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA | [b] Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA | [c] Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, USA | [d] Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence: [*] Correspondence to: Jill A. Rafael-Fortney, Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, 410 Hamilton Hall, 1645 Neil Avenue. Columbus, OH 43210, USA. Tel.: +1 614 292 7043; E-mail: [email protected].

Note: [1] These authors contributed equally.

Abstract: Background: 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. Objective: 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. Methods: 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 vivo measurements 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 measured ex vivo, followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Results: 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. Conclusions: 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.

Keywords: Spironolactone, eplerenone, lisinopril, Duchenne muscular dystrophy, mineralocorticoid receptors

DOI: 10.3233/JND-160173

Journal: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 395-404, 2016