title: Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy.
abstract: Duchenne muscular dystrophy (DMD) is an inherited disease that causes striated muscle weakness. Recently, we showed therapeutic effects of the combination of lisinopril (L), an angiotensin converting enzyme (ACE) inhibitor, and spironolactone (S), an aldosterone antagonist, in mice lacking dystrophin and haploinsufficient for utrophin (utrn(+/-);mdx, het mice); both cardiac and skeletal muscle function and histology were improved when these mice were treated early with LS. It was unknown to what extent LS treatment is effective in the most commonly used DMD murine model, the mdx mouse. In addition, current standard-of-care treatment for DMD is limited to corticosteroids. Therefore, potentially useful alternative or additive drugs need to be both compared directly to corticosteroids and tested in presence of corticosteroids. We evaluated the effectiveness of this LS combination in the mdx mouse model both compared with corticosteroid treatment (prednisolone, P) or in combination (LSP). We tested the additional combinatorial treatment containing the angiotensin II receptor blocker losartan (T), which is widely used to halt and treat the developing cardiac dysfunction in DMD patients as an alternative to an ACE inhibitor. Peak myocardial strain rate, assessed by magnetic resonance imaging, showed a negative impact of P, whereas in both diaphragm and extensor digitorum longus (EDL) muscle contractile function was not significantly impaired by P. Histologically, P generally increased cardiac damage, estimated by percentage area infiltrated by IgG as well as by collagen staining. In general, groups that only differed in the presence or absence of P (i.e. mdx vs. P, LS vs. LSP, and TS vs. TSP) demonstrated a significant detrimental impact of P on many assessed parameters, with the most profound impact on cardiac pathology.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States of America ; Dorothy M. Davis Heart & Lung Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Murray
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Schill
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Neha
authors.initials: N
authors.lastname: Rastogi
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Schultz
authors.affiliation: Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Tam
authors.initials: T
authors.lastname: Tran
authors.affiliation: Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, United States of America ; Dorothy M. Davis Heart & Lung Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Subha V
authors.initials: SV
authors.lastname: Raman
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, United States of America ; Dorothy M. Davis Heart & Lung Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004232:Diuretics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D017706:Lisinopril / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000187:drug effects; D018908:Muscle Weakness / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011239:Prednisolone / Q000009:adverse effects*; D013148:Spironolactone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D049411:Utrophin / Q000172:deficiency / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; D004232:Diuretics; D016189:Dystrophin; D005938:Glucocorticoids; D049411:Utrophin; D013148:Spironolactone; D011239:Prednisolone; D017706:Lisinopril; D019808:Losartan