Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy

PLoS One. 2014 Feb 13;9(2):e88360. doi: 10.1371/journal.pone.0088360. eCollection 2014.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiotonic Agents / antagonists & inhibitors
  • Cardiotonic Agents / pharmacology
  • Disease Models, Animal
  • Diuretics / antagonists & inhibitors
  • Diuretics / pharmacology
  • Dystrophin / deficiency
  • Dystrophin / genetics
  • Female
  • Gene Expression
  • Glucocorticoids / adverse effects*
  • Humans
  • Lisinopril / antagonists & inhibitors
  • Lisinopril / pharmacology*
  • Losartan / pharmacology
  • Male
  • Mice
  • Mice, Inbred mdx
  • Muscle Contraction / drug effects
  • Muscle Weakness / drug therapy*
  • Muscle Weakness / genetics
  • Muscle Weakness / physiopathology
  • Muscle, Skeletal / drug effects
  • Muscular Dystrophy, Animal / drug therapy*
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / physiopathology
  • Muscular Dystrophy, Duchenne
  • Myocardium / metabolism
  • Myocardium / pathology
  • Prednisolone / adverse effects*
  • Spironolactone / antagonists & inhibitors
  • Spironolactone / pharmacology*
  • Utrophin / deficiency
  • Utrophin / genetics


  • Cardiotonic Agents
  • Diuretics
  • Dystrophin
  • Glucocorticoids
  • Utrophin
  • Spironolactone
  • Prednisolone
  • Lisinopril
  • Losartan