Abstract:Muscular dystrophy has long been believed to be characterized by degeneration and abortive regeneration of muscle fibers (the muscle degeneration theory), but unfortunately its pathogenesis is still unclear and an effective treatment has yet to be developed. As a challenge to the theory, we have proposed an alternative muscle-defective-growth theory and a further bone muscle growth imbalance hypothesis supposing possible defects in bone-growth-dependent muscle growth based on our findings in hereditary dystrop… Show more
“…6d), suggesting either there is a steady rate of myonuclear addition to the fibers amongst these ages or a subset of nuclei in regenerated D2.mdx muscle do not become peripheral. Evidence of the latter has been reported in dystrophic muscle 15 and following muscle injuries 16 .…”
Section: Resultsmentioning
confidence: 93%
“…mdx muscle do not become peripheral. Evidence of the latter has been reported in dystrophic muscle 15 and following muscle injuries 16 . Figure 6 Histological time course of the development of D2.…”
Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle degenerative disease caused by loss of dystrophin protein. DMD has no cure and few treatment options. Preclinical efforts to identify potential DMD therapeutics have been hampered by lack of a small animal model that recapitulates key features of the human disease. While the dystrophin-deficient mdx mouse on the C57BL/10 genetic background (B10.mdx) is mildly affected, a more severe muscle disease is observed when the mdx mutation is crossed onto the DBA/2J genetic background (D2.mdx). In this study, the functional and histological progression of the D2.mdx skeletal muscle pathology was evaluated to determine the distinguishing features of disease. Data herein details the muscular weakness and wasting exhibited by D2.mdx skeletal muscle, as well as severe histopathological features, which include the rapid progression of fibrosis and calcifications in the diaphragm and progressive fibrosis accumulation in limb muscles. Furthermore, a timeline of D2.mdx progression is provided that details distinct stages of disease progression. These data support the D2.mdx as a superior small animal model for DMD, as compared to the B10.mdx model. The insights provided in this report should facilitate the design of preclinical evaluations for potential DMD therapeutics. Effective preclinical evaluation of potential therapeutics for human diseases requires thorough understanding of the disease phenotype exhibited by animal models utilized during such studies. Duchenne muscular dystrophy (DMD) is a fatal X-linked pediatric muscle disease with no cure and limited treatment options for affected patients. DMD is caused by mutations in the DMD gene resulting in complete loss of the gene's protein product, dystrophin 1 , a molecule that provides stabilization of the sarcolemma during muscular contraction by linking the muscle cytoskeleton and extracellular matrix 2,3. Preclinical work to study DMD has largely utilized the mdx mouse harboring a nonsense mutation in exon 23 of Dmd, which has been primarily maintained on the C57BL/10 genetic background (referred to as B10.mdx). This genetic homolog of DMD, however, exhibits a markedly mild disease phenotype compared to the human disease, limiting its potential to accurately model possible DMD therapeutics. Recent efforts to identify murine models of DMD that more accurately recapitulate the severity of the human condition than the B10.mdx mouse have led to the discovery that crossing the mdx mutation onto the DBA/2J genetic background (referred to D2.mdx) results in a more severe disease phenotype. This model exhibits greater muscle damage, impaired muscle regeneration, muscle wasting, and exacerbated progression of intramuscular fibrosis than age-matched B10.mdx mice 4-7. The heightened severity of the D2.mdx mouse has been linked to a hyper-fibrotic polymorphism in latent TGFβ binding protein (LTBP) 4 8 , which has also been identified as a genetic modifier affecting disease progression within DMD patient populations 9. For...
“…6d), suggesting either there is a steady rate of myonuclear addition to the fibers amongst these ages or a subset of nuclei in regenerated D2.mdx muscle do not become peripheral. Evidence of the latter has been reported in dystrophic muscle 15 and following muscle injuries 16 .…”
Section: Resultsmentioning
confidence: 93%
“…mdx muscle do not become peripheral. Evidence of the latter has been reported in dystrophic muscle 15 and following muscle injuries 16 . Figure 6 Histological time course of the development of D2.…”
Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle degenerative disease caused by loss of dystrophin protein. DMD has no cure and few treatment options. Preclinical efforts to identify potential DMD therapeutics have been hampered by lack of a small animal model that recapitulates key features of the human disease. While the dystrophin-deficient mdx mouse on the C57BL/10 genetic background (B10.mdx) is mildly affected, a more severe muscle disease is observed when the mdx mutation is crossed onto the DBA/2J genetic background (D2.mdx). In this study, the functional and histological progression of the D2.mdx skeletal muscle pathology was evaluated to determine the distinguishing features of disease. Data herein details the muscular weakness and wasting exhibited by D2.mdx skeletal muscle, as well as severe histopathological features, which include the rapid progression of fibrosis and calcifications in the diaphragm and progressive fibrosis accumulation in limb muscles. Furthermore, a timeline of D2.mdx progression is provided that details distinct stages of disease progression. These data support the D2.mdx as a superior small animal model for DMD, as compared to the B10.mdx model. The insights provided in this report should facilitate the design of preclinical evaluations for potential DMD therapeutics. Effective preclinical evaluation of potential therapeutics for human diseases requires thorough understanding of the disease phenotype exhibited by animal models utilized during such studies. Duchenne muscular dystrophy (DMD) is a fatal X-linked pediatric muscle disease with no cure and limited treatment options for affected patients. DMD is caused by mutations in the DMD gene resulting in complete loss of the gene's protein product, dystrophin 1 , a molecule that provides stabilization of the sarcolemma during muscular contraction by linking the muscle cytoskeleton and extracellular matrix 2,3. Preclinical work to study DMD has largely utilized the mdx mouse harboring a nonsense mutation in exon 23 of Dmd, which has been primarily maintained on the C57BL/10 genetic background (referred to as B10.mdx). This genetic homolog of DMD, however, exhibits a markedly mild disease phenotype compared to the human disease, limiting its potential to accurately model possible DMD therapeutics. Recent efforts to identify murine models of DMD that more accurately recapitulate the severity of the human condition than the B10.mdx mouse have led to the discovery that crossing the mdx mutation onto the DBA/2J genetic background (referred to D2.mdx) results in a more severe disease phenotype. This model exhibits greater muscle damage, impaired muscle regeneration, muscle wasting, and exacerbated progression of intramuscular fibrosis than age-matched B10.mdx mice 4-7. The heightened severity of the D2.mdx mouse has been linked to a hyper-fibrotic polymorphism in latent TGFβ binding protein (LTBP) 4 8 , which has also been identified as a genetic modifier affecting disease progression within DMD patient populations 9. For...
BACKGROUND & AIMS
Duchenne muscular dystrophy is a debilitating genetic disorder characterized by severe muscle wasting and early death in afflicted boys. The primary cause of this disease is mutations in the dystrophin gene resulting in massive muscle degeneration and inflammation. The purpose of this study was to determine if dystrophic muscle pathology and inflammation were decreased by pre-natal and early dietary intervention with green tea extract.
METHODS
Mdx breeder mice and pups were fed diets containing 0.25% or 0.5% green tea extract and compared to untreated mdx and C57BL/6J mice. Serum creatine kinase was assessed as a systemic indicator of muscle damage. Quantitative histopathological and immunohistochemical techniques were used to determine muscle pathology, macrophage infiltration, and NF-κB localization.
RESULTS
Early treatment of mdx mice with green tea extract significantly decreased serum creatine kinase by ~85% at age 42 days (P≤0.05). In these mice, the area of normal fiber morphology was increased by as much as ~32% (P≤0.05). The primary histopathological change was a ~21% decrease in the area of regenerating fibers (P≤0.05). NF-κB staining in regenerating muscle fibers was also significantly decreased in green tea extract-treated mdx mice when compared to untreated mdx mice.
CONCLUSION
Early treatment with green tea extract decreases dystrophic muscle pathology potentially by regulating NF-κB activity in regenerating muscle fibers.
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