TGF-β–driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model

Mázala, Davi A. G.; Novak, James S.; Hogarth, Marshall W.; Nearing, Marie; Adusumalli, Prabhat; Tully, Christopher B.; Habib, Nayab F.; Gordish‐Dressman, Heather; Chen, Yi Wen; Jaiswal, Jyoti K.; Partridge, Terence A.

doi:10.1172/jci.insight.135703

Cited by 105 publications

(132 citation statements)

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“…The prevalence of muscle fibers containing centrally-located nuclei, often used as an indicator of muscle regeneration 13 , is significantly reduced in both the D2.mdx diaphragm and gastroc, as compared to B10.mdx muscles ( Fig. 3), consistent with reports of reduced muscle regeneration associated with the DBA/2J genetic background [5][6][7] . As detailed in a previous report 14 , intramuscular calcifications are also a feature of D2.mdx skeletal muscle and can be visualized using Alizarin red staining (AR).…”

Section: Resultssupporting

confidence: 84%

“…This time course differs from that of the B10.mdx model, where inflammatory degeneration of skeletal muscle is most prominent at ~ 1 mo 22,23 . While it is not currently clear what specifically initiates the inflammation or degeneration in the early ages of murine DMD models, the severe fibrogenic aspect of the post-degenerative stage likely arises from a combination of regenerative asynchrony associated with the degenerative stage, as early and late muscle regeneration signals co-exist within the same muscle due to unsynchronized degeneration 24 , and less robust myogenesis associated with the DBA2/J genetic background, as compared to C57-based background strains [5][6][7] . In agreement with this hypothesis, similar exacerbated muscle fibrosis phenotypes can also be induced in mdx of the C57BL/6 background by incurring repeated injuries 25 , which can promote both regenerative asynchrony and satellite cell depletion.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence suggests that these features, which have also been reported in DMD patient muscle biopsies 21 , express osteogenic markers, develop early in the D2. mdx disease progression from fibro-adipogenic progenitor cells, and dissipate at later stages of disease progression 6 , 14 . Their presence does, however, interfere with the histological measurement of intramuscular fibrosis using PSR and TC staining.…”

Section: Discussionmentioning

confidence: 99%

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The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy

Hammers

Hart

Matheny

et al. 2020

Sci Rep

102

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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...

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy

Hammers

Hart

Matheny

et al. 2020

Sci Rep

102

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“…Based on the recently published articles, it seems that enhanced activity of TGF-β predisposes muscle into damage. The TGF-β elevates the levels of fibroadipogenic progenitors (FAPs) to induce fibro-calcification of muscle, resulting in muscle degeneration and inhibition of regenerative myogenesis ( Mazala et al, 2020 ). In respect to the role of TGF-β in degeneration, studies have focused on regulation of TGF-β signaling in disease therapy.…”

Section: Transforming Growth Factor-beta Signaling Pathway: From Basimentioning

confidence: 99%

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

et al. 2020

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Immune response, proliferation, migration and angiogenesis are juts a few of cellular events that are regulated by transforming growth factor-β (TGF-β) in cells. A number of studies have documented that TGF-β undergoes abnormal expression in different diseases, e.g., diabetes, cancer, fibrosis, asthma, arthritis, among others. This has led to great fascination into this signaling pathway and developing agents with modulatory impact on TGF-β. Curcumin, a natural-based compound, is obtained from rhizome and roots of turmeric plant. It has a number of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor, anti-diabetes and so on. Noteworthy, it has been demonstrated that curcumin affects different molecular signaling pathways such as Wnt/β-catenin, Nrf2, AMPK, mitogen-activated protein kinase and so on. In the present review, we evaluate the potential of curcumin in regulation of TGF-β signaling pathway to corelate it with therapeutic impacts of curcumin. By modulation of TGF-β (both upregulation and down-regulation), curcumin ameliorates fibrosis, neurological disorders, liver disease, diabetes and asthma. Besides, curcumin targets TGF-β signaling pathway which is capable of suppressing proliferation of tumor cells and invading cancer cells.

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“…Therefore, based on our findings, it could be of interest to evaluate the impact of LTBP4 as modifier gene in PD subjects and its relevance as new therapeutic target. Interestingly, multiple strategies could be exploited to counteract the increased release of TGFβ from the extracellular matrix, as determined by the “detrimental” Ltbp4 Δ36 allele [ 42 , 71 , [80] , [81] , [82] , [83] ].…”

Section: Discussionmentioning

confidence: 99%

Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects

et al. 2020

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Background Pompe disease (PD) is a neuromuscular disorder caused by deficiency of acidalpha-glucosidase (GAA), leading to motor and respiratory dysfunctions. Available Gaa knock-out (KO) mouse models do not accurately mimic PD, particularly its highly impaired respiratory phenotype. Methods Here we developed a new mouse model of PD crossing Gaa KO B6;129 with DBA2/J mice. We subsequently treated Gaa KO DBA2/J mice with adeno-associated virus (AAV) vectors expressing a secretable form of GAA (secGAA). Findings Male Gaa KO DBA2/J mice present most of the key features of the human disease, including early lethality, severe respiratory impairment, cardiac hypertrophy and muscle weakness. Transcriptome analyses of Gaa KO DBA2/J , compared to the parental Gaa KO B6;129 mice, revealed a profoundly impaired gene signature in the spinal cord and a similarly deregulated gene expression in skeletal muscle. Muscle and spinal cord transcriptome changes, biochemical defects, respiratory and muscle function in the Gaa KO DBA2/J model were significantly improved upon gene therapy with AAV vectors expressing secGAA. Interpretation These data show that the genetic background impacts on the severity of respiratory function and neuroglial spinal cord defects in the Gaa KO mouse model of PD. Our findings have implications for PD prognosis and treatment, show novel molecular pathophysiology mechanisms of the disease and provide a unique model to study PD respiratory defects, which majorly affect patients. Funding This work was supported by Genethon, the French Muscular Dystrophy Association (AFM), the European Commission (grant nos. 667751, 617432, and 797144), and Spark Therapeutics.

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TGF-β–driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model

Cited by 105 publications

References 50 publications

The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy

The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects

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