Relative roles of TGF-β1 and Wnt in the systemic regulation and aging of satellite cell responses

Department of Bioengineering, University of California-Berkeley, Berkeley, CA 94720, USA.
Aging cell (Impact Factor: 6.34). 10/2009; 8(6):676-89. DOI: 10.1111/j.1474-9726.2009.00517.x
Source: PubMed

ABSTRACT Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged P-Smad3, differentiated niche, and by the aged circulation. With respect to muscle fibers, we previously established that a shift from active Notch to excessive transforming growth factor-beta (TGF-beta) induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses. In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt. Here, we examined the age-dependent myogenic activity of sera TGF-beta1, and its potential cross-talk with systemic Wnt. We found that sera TGF-beta1 becomes elevated within aged humans and mice, while systemic Wnt remained undetectable in these species. Wnt also failed to inhibit satellite cell myogenicity, while TGF-beta1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-beta1 were inhibitory and young sera suppressed myogenesis if TGF-beta1 was activated. Our data suggest that platelet-derived sera TGF-beta1 levels, or endocrine TGF-beta1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-beta neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-beta1 and rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-beta receptor kinase inhibitor, which attenuated TGF-beta signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-beta1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-beta1, and introduce new therapeutic strategies for the broad restoration of aged organ repair.

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Available from: Anshu Agrawal, Sep 27, 2015
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    • "Whereas Klotho depletion resulted in increased renal fibrosis, Klotho replacement therapy significantly alleviated the pathology, suggesting that decreased Klotho levels may contribute to the pathogenesis of renal fibrosis (Doi et al., 2011). Accordingly, systemic administration of a TGF-β1 receptor 1 (R1) kinase inhibitor effectively enhanced myofiber regeneration after injury, whereas application of a TGF-β1 neutralizing antibody had no effect (Carlson et al., 2009b). These findings support the above stated hypothesis that a natural decoy of TGF-β1 signaling may minimize activation of fibrogenic pathways in young animals following skeletal muscle injury, but that this suppression is lost in aged animals. "
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    Frontiers in Physiology 06/2014; 5:189. DOI:10.3389/fphys.2014.00189 · 3.53 Impact Factor
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    • "Another factor enriched in aged niches is TGFβ, which has been shown to be increased in blood (Challen et al., 2010) and muscle (Carlson et al., 2009) and leads to aging phenotypes. Levels of TGFβ increase in endothelial cells of the NSC niche during aging and after exposure to IR (Pineda et al., 2013). "
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    Current Topics in Developmental Biology 01/2014; 107C:405-438. DOI:10.1016/B978-0-12-416022-4.00014-7 · 4.68 Impact Factor
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    • "While most studies reported negative regulatory role of TGF-β1 in myogenesis, others showed that TGF-β1 plays an essential role in muscle regeneration [47], [48], [49]. This conditional muscle-specific mouse model provides a useful tool for examining the regulatory roles of TGF-β1 in skeletal muscles and for developing strategies to modulate TGF-β1 in muscles. "
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    ABSTRACT: To study the effects of transforming growth factor beta 1 (TGF-β1) on fibrosis and failure of regeneration of skeletal muscles, we generated a tet-repressible muscle-specific TGF-β1 transgenic mouse in which expression of TGF-β1 is controlled by oral doxycycline. The mice developed muscle weakness and atrophy after TGF-β1 over-expression. We defined the group of mice that showed phenotype within 2 weeks as early onset (EO) and the rest as late onset (LO), which allowed us to further examine phenotypic differences between the groups. While only mice in the EO group showed significant muscle weakness, pathological changes including endomysial fibrosis and smaller myofibers were observed in both groups at two weeks after the TGF-β1 was over-expressed. In addition, the size of the myofibers and collagen accumulation were significantly different between the two groups. The amount of latent and active TGF-β1 in the muscle and circulation were significantly higher in the EO group compared to the LO or control groups. The up-regulation of the latent TGF-β1 indicated that endogenous TGF-β1 was induced by the expression of the TGF-β1 transgene. Our studies showed that the primary effects of TGF-β1 over-expression in skeletal muscles are muscle wasting and endomysial fibrosis. In addition, the severity of the pathology is associated with the total amount of TGF-β1 and the expression of endogenous TGF-β1. The findings suggest that an auto-feedback loop of TGF-β1 may contribute to the severity of phenotypes.
    PLoS ONE 11/2013; 8(11):e79356. DOI:10.1371/journal.pone.0079356 · 3.23 Impact Factor
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