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-β) 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-β1, and its potential cross-talk with systemic Wnt. We found that sera TGF-β1 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-β1 suppressed regenerative potential in a biphasic fashion. Intriguingly, young levels of TGF-β1 were inhibitory and young sera suppressed myogenesis if TGF-β1 was activated. Our data suggest that platelet-derived sera TGF-β1 levels, or endocrine TGF-β1 levels, do not explain the age-dependent inhibition of muscle regeneration by this cytokine. In vivo, TGF-β neutralizing antibody, or a soluble decoy, failed to reduce systemic TGF-β1 and rescue myogenesis in old mice. However, muscle regeneration was improved by the systemic delivery of a TGF-β receptor kinase inhibitor, which attenuated TGF-β signaling in skeletal muscle. Summarily, these findings argue against the endocrine path of a TGF-β1-dependent block on muscle regeneration, identify physiological modalities of age-imposed changes in TGF-β1, and introduce new therapeutic strategies for the broad restoration of aged organ repair.
Highlights
Adult skeletal muscle robustly regenerates throughout an organism’s life but, with advancing age, its ability to repair diminishes and fails (Grounds, 1998; Renault et al, 2002)
The regenerative capacity of aged muscle can be enhanced by exposing old satellite cells to young systemic factors – such as when young and old mice are physically connected to share blood circulation, or when aged satellite cells are cultured in the presence of young sera (Conboy et al, 2005; Carlson & Conboy, 2007a)
In addition to other cytokines (e.g. IGF-1, TNF-a, IL-6, etc.) many of these have been implicated in the process of aging, and with respect to muscle regeneration (Grounds, 2002; Moresi et al, 2008; Dorshkind et al, 2009)
Summary
Adult skeletal muscle robustly regenerates throughout an organism’s life but, with advancing age, its ability to repair diminishes and fails (Grounds, 1998; Renault et al, 2002). Diminished satellite cell numbers have been implicated in the age-related decline of muscle tissue regeneration, several reports identified key molecular changes within Notch and P-Smad signaling in the aged endogenous populations (Conboy et al, 2003; Carlson & Conboy, 2007b; Carlson et al, 2008). In this regard, aging of the satellite cell micro-niche was found to promote underproduction of Notch ligand Delta, and overproduction of transforming growth factor-beta (TGF-b). In addition to local tissue niches, systemic factors in sera regulate the regenerative responses of organ stem cells and importantly, the aged circulation inhibits the regenerative potential of even young satellite cells
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