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1.
Elife ; 112022 03 24.
Article in English | MEDLINE | ID: mdl-35323108

ABSTRACT

In skeletal muscle, transforming growth factor-ß (TGF-ß) family growth factors, TGF-ß1 and myostatin, are involved in atrophy and muscle wasting disorders. Simultaneous interference with their signalling pathways may improve muscle function; however, little is known about their individual and combined receptor signalling. Here, we show that inhibition of TGF-ß signalling by simultaneous muscle-specific knockout of TGF-ß type I receptors Tgfbr1 and Acvr1b in mice, induces substantial hypertrophy, while such effect does not occur by single receptor knockout. Hypertrophy is induced by increased phosphorylation of Akt and p70S6K and reduced E3 ligases expression, while myonuclear number remains unaltered. Combined knockout of both TGF-ß type I receptors increases the number of satellite cells, macrophages and improves regeneration post cardiotoxin-induced injury by stimulating myogenic differentiation. Extra cellular matrix gene expression is exclusively elevated in muscle with combined receptor knockout. Tgfbr1 and Acvr1b are synergistically involved in regulation of myofibre size, regeneration, and collagen deposition.


Subject(s)
Muscle Development , Muscle, Skeletal , Animals , Hypertrophy , Mice , Muscle, Skeletal/metabolism , Receptor, Transforming Growth Factor-beta Type I/metabolism , Transforming Growth Factor beta/metabolism
2.
Biochem Biophys Res Commun ; 547: 176-182, 2021 04 02.
Article in English | MEDLINE | ID: mdl-33618224

ABSTRACT

Skeletal muscle fibrosis and regeneration are modulated by transforming growth factor ß (TGF-ß) superfamily. Amongst them, TGF-ß1 is a highly potent pro-fibrotic factor, while TGF-ß3 has been implicated to reduce scar formation and collagen production in skin and vocal mucosa. However, little is known about the individual and combined short- and long-term effects of TGF-ß1 and TGF-ß3 on collagen expression in myoblasts and myotubes. Here we show that in C2C12 myoblasts TGF-ß1 and/or TGF-ß3 increased mRNA expression of Ctgf and Fgf-2 persistently after 3 h and of Col1A1 after 24 h, while TGF-ß1+TGF-ß3 mitigated these effects after 48 h incubation. Gene expression of Tgf-ß1 was enhanced by TGF-ß1 and/or TGF-ß3 after 24 h and 48 h. However, Tgfbr1 mRNA expression was reduced at 48 h. After 48 h incubation with TGF-ß1 and/or TGF-ß3, Col3A1 and Col4A1 mRNA expression levels were decreased. Myoblasts produced collagen after three days incubation with TGF-ß1 and/or TGF-ß3 in a dose independent manner. Collagen deposition was doubled when myoblasts differentiated into myotubes and TGF-ß1 and/or TGF-ß3 did not stimulate collagen production any further. TGF-ß type I receptor (TGFBR1) inhibitor, LY364947, suppressed TGF-ßs-induced collagen production. Collagen I expression was higher in myotubes than in myoblasts. TGF-ß1 and/or TGF-ß3 inhibited myotube differentiation which was antagonized by LY364947. These results indicate that both C2C12 myoblasts and myotubes produce collagen. Whereas TGF-ß1 and TGF-ß3 individually and simultaneously stimulate collagen production in C2C12 differentiating myoblasts, in myotubes these effects are less prominent. In muscle cells, TGF-ß3 is ineffective to antagonize TGF-ß1-induced collagen production.


Subject(s)
Collagen/biosynthesis , Muscle Fibers, Skeletal/drug effects , Myoblasts/drug effects , Transforming Growth Factor beta1/pharmacology , Transforming Growth Factor beta3/pharmacology , Animals , Cell Differentiation/drug effects , Cell Line , Collagen/metabolism , Drug Synergism , Mice , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/metabolism , Myoblasts/cytology , Myoblasts/metabolism
3.
Cells ; 9(2)2020 02 06.
Article in English | MEDLINE | ID: mdl-32041253

ABSTRACT

Transforming Growth Factor ß (TGF-ß) is involved in fibrosis as well as the regulation of muscle mass, and contributes to the progressive pathology of muscle wasting disorders. However, little is known regarding the time-dependent signalling of TGF-ß in myoblasts and myotubes, as well as how TGF-ß affects collagen type I expression and the phenotypes of these cells. Here, we assessed effects of TGF-ß on gene expression in C2C12 myoblasts and myotubes after 1, 3, 9, 24 and 48 h treatment. In myoblasts, various myogenic genes were repressed after 9, 24 and 48 h, while in myotubes only a reduction in Myh3 expression was observed. In both myoblasts and myotubes, TGF-ß acutely induced the expression of a subset of genes involved in fibrosis, such as Ctgf and Fgf-2, which was subsequently followed by increased expression of Col1a1. Knockdown of Ctgf and Fgf-2 resulted in a lower Col1a1 expression level. Furthermore, the effects of TGF-ß on myogenic and fibrotic gene expression were more pronounced than those of myostatin, and knockdown of TGF-ß type I receptor Tgfbr1, but not receptor Acvr1b, resulted in a reduction in Ctgf and Col1a1 expression. These results indicate that, during muscle regeneration, TGF-ß induces fibrosis via Tgfbr1 by stimulating the autocrine signalling of Ctgf and Fgf-2.


Subject(s)
Collagen Type I/metabolism , Connective Tissue Growth Factor/metabolism , Fibroblast Growth Factor 2/metabolism , Muscle Fibers, Skeletal/metabolism , Myoblasts/metabolism , Transforming Growth Factor beta/pharmacology , Animals , Cell Differentiation/drug effects , Cell Size/drug effects , Cells, Cultured , Fibrosis , Gene Expression Regulation/drug effects , Mice, Inbred C57BL , Models, Biological , Muscle Development/drug effects , Muscle Development/genetics , Muscle Fibers, Skeletal/drug effects , Myoblasts/drug effects , Myostatin/pharmacology , Receptor, Transforming Growth Factor-beta Type I/metabolism , Time Factors
4.
Cell Rep ; 17(6): 1683-1698, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27806305

ABSTRACT

Histone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions. Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons. Here, we report that the NuRD complex, which couples ATP-dependent chromatin remodeling with histone deacetylase activity, regulates mouse brain development. Subunit exchange of CHDs, the core ATPase subunits of the NuRD complex, is required for distinct aspects of cortical development. Whereas CHD4 promotes the early proliferation of progenitors, CHD5 facilitates neuronal migration and CHD3 ensures proper layer specification. Inhibition of each CHD leads to defects of neuronal differentiation and migration, which cannot be rescued by expressing heterologous CHDs. Finally, we demonstrate that NuRD complexes containing specific CHDs are recruited to regulatory elements and modulate the expression of genes essential for brain development.


Subject(s)
Cerebral Cortex/embryology , Cerebral Cortex/metabolism , Chromatin Assembly and Disassembly , Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism , Protein Subunits/metabolism , Animals , Cell Cycle , Cell Movement , Gene Deletion , Gene Expression Regulation, Developmental , Mice, Inbred C57BL , Microcephaly/pathology , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Promoter Regions, Genetic/genetics
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