Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, United States AJP Heart and Circulatory Physiology
(Impact Factor: 3.84).
01/2006; 289(6):H2373-8. DOI: 10.1152/ajpheart.00448.2005
The loss of dystrophin in patients with Duchenne muscular dystrophy (DMD) causes devastating skeletal muscle degeneration and cardiomyopathy. Dystrophin-deficient (mdx) mice have a much milder phenotype, whereas double knockout (DKO) mice lacking both dystrophin and its homolog, utrophin, exhibit the clinical signs observed in DMD patients. We have previously shown that DKO and mdx mice have similar severities of histological features of cardiomyopathy, but no contractile functional measurements of DKO heart have ever been carried out. To investigate whether DKO mice display cardiac dysfunction at the tissue level, contractile response of the myocardium was tested in small, unbranched, ultrathin, right ventricular muscles. Under near physiological conditions, peak isometric active developed tension (F(dev), in mN/mm2) at a stimulation frequency of 4 Hz was depressed in DKO mice (15.3 +/- 3.7, n = 8) compared with mdx mice (24.2 +/- 5.4, n = 7), which in turn were depressed compared with wild-type (WT) control mice (33.2 +/- 4.5, n = 7). This reduced Fdev was also observed at frequencies within the murine physiological range; at 12 Hz, Fdev was (in mN/mm2) 11.4 +/- 1.8 in DKO, 14.5 +/- 4.2 in mdx, and 28.8 +/- 5.4 in WT mice. The depression of Fdev was observed over the entire frequency range of 4-14 Hz and was significant between DKO versus mdx mice, as well as between DKO or mdx mice versus WT mice. Under beta-adrenergic stimulation (1 micromol/l isoproterenol), Fdev in DKO preparations was only (in mN/mm2) 14.7 +/- 5.1 compared with 30.9 +/- 8.9 in mdx and 41.0 +/- 4.9 in WT mice. These data show that cardiac contractile dysfunction of mdx mice is generally worsened in mice also lacking utrophin.
Available from: PubMed Central
- "In addition, overexpression of utrophin was shown to rescue the muscular dystrophy phenotype in mouse models of DMD (Tinsley et al. 1996, 1998), including the dko mouse (Wakefield et al. 2000). This protective role for utrophin upregulation is also consistent with the more severe phenotype seen in the dko mice that lack both dystrophin and utrophin (Deconinck et al. 1998; Rafael et al. 1998; Janssen et al. 2005). In the current study muscle performance between the WT and mdx mice differed from the pattern seen in the mdx:utrophin +/À mice at 6 and 12 months of age. "
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ABSTRACT: The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin(+/-) mice compared to mdx mice at 12 months. Mdx:utrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdx:utrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus.
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
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- "Given these constraints, the mild phenotype of the mdx mice prevents a detailed quantitative comparison of individual parameters. Now that the same trend in the potential efficacy with lisinopril/spironolactone for dystrophic cardiac and skeletal muscles was replicated in this study with the genotypic mdx model, future studies would ideally be performed in more severely affected dystrophic mice as used by us and others in the past , , , . Use of models with deficits in skeletal and cardiac function and pathology more similar to patients can be used to avoid the logistical and financial complications of the extremely large group sizes or lengthy study needed to tease out therapeutic effects in less affected mdx mice. "
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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.
Available from: PubMed Central
- "Dystrophin-deficient (mdx) mice, in which the dystrophin gene is mutated, are widely used as a model of DMD, and genetic deletion of utrophin superimposed on the mdx background greatly worsens the observed dystrophy, consistent with redundant function between utrophin and dystrophin
[10-15]. The dystrophin utrophin double knock-out mouse (mdx/utrn-/-) models the severity of human DMD phenotype more faithfully than the parental dystrophin knock-out (mdx) mouse
[11,12,15]. Conversely, transgenic expression of utrophin in skeletal muscle significantly improves indices of dystrophy in mdx mice
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ABSTRACT: Duchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha improves skeletal muscle function in the murine "mdx" model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1alpha include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction.
The effects of transgenic overexpression of PGC-1beta, a homolog of PGC-1alpha in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1alpha confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1alpha transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1alpha overexpression on muscle structure and function in mdx mice.
We show here that PGC-1beta does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1beta transgenesis protects as efficaciously as PGC-1alpha against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1alpha is overexpressed in mdx/utrn-/- mice, we find that PGC-1alpha dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1alpha overexpression to show that PGC-1alpha can protect against dystrophy even if activated post-natally, a more plausible therapeutic option.
These data demonstrate that PGC-1alpha can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1alpha is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1beta as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1alpha and PGC-1beta protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.
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