Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice

Accornero, Federica; Kanisicak, Onur; Tjondrokoesoemo, Andoria; Attia, Aria C.; McNally, Elizabeth M.; Molkentin, Jeffery D.

doi:10.1093/hmg/ddu413

Cited by 48 publications

(48 citation statements)

References 54 publications

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“…These results are consistent with results obtained by Accornero et al . () showing that TGF‐β1 increases myofiber membrane fragility through a reactive oxygen species‐dependent mechanism, resulting in greater myofiber necrosis. A larger number of necrotic myofibers in injured muscles at day 7 after injury suggests impaired phagocytic function of macrophages (Zhao et al .…”

Section: Discussionmentioning

confidence: 99%

Effects of transforming growth factor‐β1 treatment on muscle regeneration and adipogenesis in glycerol‐injured muscle

Mahdy

Warita

Hosaka

2017

Animal Science Journal

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Transforming growth factor (TGF)-β1 is associated with fibrosis in many organs. Recent studies demonstrated that delivery of TGF-β1 into chemically injured muscle enhances fibrosis. In this study, we investigated the effects of exogenous TGF-β1 on muscle regeneration and adipogenesis in glycerol-injured muscle of normal mice. Tibialis anterior (TA) muscles were injured by glycerol injection. TGF-β1 was either co-injected with glycerol, as an 'early treatment' group, or injected at day 4 after glycerol, as a 'late treatment' group and the TA muscles were collected at day 7 after initial injury. Myotube density was significantly lower in the early treatment group than in the glycerol-injured group (without TGF-β1 treatment). Moreover, the Oil red O-positive area was significantly smaller in the early treatment group than in the late treatment group and glycerol-injured group. Furthermore, TGF-β1 treatment increased endomysial fibrosis and induced immunostaining of α-smooth muscle actin. The greater inhibitory effects of early TGF-β1 treatment than that of late TGF-β1 treatment during regeneration in glycerol-injured muscle suggest a more potent effect of TGF-β1 on the initial stage of muscle regeneration and adipogenesis. Combination of TGF-β1 with glycerol might be an alternative to enhance muscle fibrosis for future studies.

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Section: Discussionmentioning

confidence: 99%

Effects of transforming growth factor‐β1 treatment on muscle regeneration and adipogenesis in glycerol‐injured muscle

Mahdy

Warita

Hosaka

2017

Animal Science Journal

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“…Expression of a dominant negative TGF-b receptor (TGF-bR) and administration of a TGF-b neutralizing antibody both reduced mdx muscle fibrosis. 18,19 Conversely, muscle-specific TGF-b1 overexpression in transgenic mice yielded increased fibrosis and muscular atrophy. 20 Expression of TGF-beinducible early gene 1 [alias Krüppellike factor 10 (KLF10)] is induced soon after cell exposure to TGF-b.…”

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confidence: 99%

KLF10 Gene Expression Modulates Fibrosis in Dystrophic Skeletal Muscle

DiMario

2018

The American Journal of Pathology

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Dystrophic skeletal muscle is characterized by fibrotic accumulation of extracellular matrix components that compromise muscle structure, function, and capacity for regeneration. Tissue fibrosis is often initiated and sustained through transforming growth factor-β (TGF-β) signaling, and Krüppel-like factor 10 (KLF10) is an immediate early gene that is transcriptionally activated in response to TGF-β signaling. It encodes a transcriptional regulator that mediates the effects of TGF-β signaling in a variety of cell types. This report presents results of investigation of the effects of loss of KLF10 gene expression in wild-type and dystrophic (mdx) skeletal muscle. On the basis of RT-PCR, Western blot, and histological analyses of mouse tibialis anterior and diaphragm muscles, collagen type I (Col1a1) and fibronectin gene expression and protein deposition were increased in KLF10 mice, contributing to increased fibrosis. KLF10 mice displayed increased expression of genes encoding SMAD2, SMAD3, and SMAD7, particularly in diaphragm muscle. SMAD4 gene expression was unchanged. Expression of the extracellular matrix remodeling genes, MMP2 and TIMP1, was also increased in KLF10-deficient mouse muscle. Histological analyses and assays of hydroxyproline content indicated that the loss of KLF10 increased fibrosis. Dystrophic KLF10-null mice also had reduced grip strength. The effects of loss of KLF10 gene expression were most pronounced in dystrophic diaphragm muscle, suggesting that KLF10 moderates the fibrotic effects of TGF-β signaling in chronically damaged regenerating muscle.

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“…SMAD7 has been shown to act as a TGFβ intracellular antagonist against myostatin, and mice null for SMAD7 have decreased muscle mass, force generation, and regeneration [22]. A dominant-negative mutation in Tgfbr2 expressed transgenically in muscle fibers improved muscle function in a mouse model of muscular dystrophy suggesting that hyper-TGFβ signaling contributes to muscular dystrophy pathology [23]. Furthermore, antisense oligonucleotides directed against the TGFβ Type I Receptor (ALK5) in the mdx mouse have been shown to reduce expression of genes related to fibrosis including Col1a1 , Ctgf , and Serpine1 and, at the same time, increase expression of Myog1, a marker of regeneration [24].…”

Section: The Tgfβ Pathway In Muscle and Muscle Diseasementioning

confidence: 99%

Modifier genes and their effect on Duchenne muscular dystrophy

McNally²

2015

Current Opinion in Neurology

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Purpose of Review Recently, genetic pathways that modify the clinical severity of Duchenne Muscular Dystrophy have been identified. The pathways uncovered as modifiers are useful to predict prognosis and also elucidate molecular signatures that can be manipulated therapeutically. Recent Findings Modifiers have been identified using combinations of transcriptome and genome profiling. Osteopontin, encoded by the SPP1 gene, was found using gene expression profiling. LTBP4, encoding latent transforming growth factor β binding protein 4 was initially discovered using a genomewide screen in mice and then validated in cohorts of Duchenne Muscular Dystrophy patients. These two pathways converge in that they both regulate TGFβ. A third modifier, Anxa6 that specifies annexin A6, is a calcium binding protein has been identified using mouse models, and regulates the injury pathway and sarcolemmal resealing. Summary Genetic modifiers can serve as biomarkers for outcomes in Duchenne Muscular Dystrophy. Modifiers can alter strength and ambulation in muscular dystrophy, and these same features can be used as endpoints used in clinical trials. Moreover, because genetic modifiers can influence outcomes, these genetic markers should be considered when stratifying results in muscular dystrophy.

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Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice

Cited by 48 publications

References 54 publications

Effects of transforming growth factor‐β1 treatment on muscle regeneration and adipogenesis in glycerol‐injured muscle

Effects of transforming growth factor‐β1 treatment on muscle regeneration and adipogenesis in glycerol‐injured muscle

KLF10 Gene Expression Modulates Fibrosis in Dystrophic Skeletal Muscle

Modifier genes and their effect on Duchenne muscular dystrophy

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