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The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy.

ABSTRACT: Although it has been speculated that stem cell depletion plays a role in the rapid progression of the muscle histopathology associated with Duchenne Muscular Dystrophy (DMD), the molecular and cellular mechanisms responsible for stem cell depletion remain poorly understood. The rapid depletion of muscle stem cells has not been observed in the dystrophin-deficient model of DMD (mdx mouse), which may explain the relatively mild dystrophic phenotype observed in this animal model. In contrast, we have observed a rapid occurrence of stem cell depletion in the dystrophin/utrophin double knockout (dKO) mouse model, which exhibits histopathological features that more closely recapitulate the phenotype observed in DMD patients compared with the mdx mouse. Notch signaling has been found to be a key regulator of stem cell self-renewal and myogenesis in normal skeletal muscle; however, little is known about the role that Notch plays in the development of the dystrophic histopathology associated with DMD. Our results revealed an over-activation of Notch in the skeletal muscles of dKO mice, which correlated with sustained inflammation, impaired muscle regeneration and the rapid depletion and senescence of the muscle progenitor cells (MPCs, i.e. Pax7+ cells). Consequently, the repression of Notch in the skeletal muscle of dKO mice delayed/reduced the depletion and senescence of MPCs, and restored the myogenesis capacity while reducing inflammation and fibrosis. We suggest that the down-regulation of Notch could represent a viable approach to reduce the dystrophic histopathologies associated with DMD.

SUBMITTER: Mu X

PROVIDER: S-EPMC4406301 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy.

Mu Xiaodong X Tang Ying Y Lu Aiping A Takayama Koji K Usas Arvydas A Wang Bing B Weiss Kurt K Huard Johnny J

Human molecular genetics 20150212 10

Although it has been speculated that stem cell depletion plays a role in the rapid progression of the muscle histopathology associated with Duchenne Muscular Dystrophy (DMD), the molecular and cellular mechanisms responsible for stem cell depletion remain poorly understood. The rapid depletion of muscle stem cells has not been observed in the dystrophin-deficient model of DMD (mdx mouse), which may explain the relatively mild dystrophic phenotype observed in this animal model. In contrast, we ha ...[more]

PMID: 25678553

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Project description:BACKGROUND:Fukutin-related protein (FKRP) mutations are the most common cause of dystroglycanopathies known to cause both limb girdle and congenital muscular dystrophy. The P448Lneo- mouse model has a knock-in mutation in the FKRP gene and develops skeletal, respiratory, and cardiac muscle disease. METHODS:We studied the natural history of the P448Lneo- mouse model over 9 months and the effects of twice weekly treadmill running. Forelimb and hindlimb grip strength (Columbus Instruments) and overall activity (Omnitech Electronics) assessed skeletal muscle function. Echocardiography was performed using VisualSonics Vevo 770 (FujiFilm VisualSonics). Plethysmography was performed using whole body system (ADInstruments). Histological evaluations included quantification of inflammation, fibrosis, central nucleation, and fiber size variation. RESULTS:P448Lneo- mice had significantly increased normalized tissue weights compared to controls at 9 months of age for the heart, gastrocnemius, soleus, tibialis anterior, quadriceps, and triceps. There were no significant differences seen in forelimb or hindlimb grip strength or activity monitoring in P448Lneo- mice with or without exercise compared to controls. Skeletal muscles demonstrated increased inflammation, fibrosis, central nucleation, and variation in fiber size compared to controls (p <?0.05) and worsened with exercise. Plethysmography showed significant differences in respiratory rates and decreased tidal and minute volumes in P448Lneo- mice (p <?0.01). There was increased fibrosis in the diaphragm compared to controls (p <?0.01). Echocardiography demonstrated decreased systolic function in 9-month-old mutant mice (p <?0.01). There was increased myocardial wall thickness and mass (p <?0.001) with increased fibrosis in 9-month-old P448Lneo- mice compared to controls (p <?0.05). mRNA expression for natriuretic peptide type A (Nppa) was significantly increased in P448Lneo- mice compared to controls at 6 months (p <?0.05) and for natriuretic peptide type B (Nppb) at 6 and 9 months of age (p <?0.05). CONCLUSIONS:FKRP-deficient P448Lneo- mice demonstrate significant deficits in cardiac and respiratory functions compared to control mice, and this is associated with increased inflammation and fibrosis. This study provides new functional outcome measures for preclinical trials of FKRP-related muscular dystrophies.

Dataset Information

The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy.

Publications

The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy.

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