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: 5.94). 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, Aug 10, 2015
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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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    • "Wnt7a promotes the symmetric expansion of satellite cells without affecting the growth or differentiation of myoblasts and controls satellite cell number following regeneration. The systemic role of Wnt in satellite muscle regeneration has been challenged by showing that Wnt activity was not present in sera, did not contribute to the TGF-beta1-dependent inhibition of satellite cell myogenic potential and did not improve the regeneration of old muscle in vivo (Carlson et al. 2009). "
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