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

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.

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

“…Under normal conditions, without any stimuli, TGF-b1/ p-Smad signaling may be downregulated either by serum latent TGF-b1 or by lower levels of TGF-b1 receptors, whereas upon injury such as oxidative stress, aging, inflammation and so on, the active TGF-b1 and/or the expression of TGF-b1 receptor may be increased, thereby causing pSmad signaling to accelerate in HSCs. 41 MAP kinase activation in livers was associated with the extent of the liver injury and fibrosis. JNK has a role in CCl 4 -induced liver damage by stimulating the production of pro-inflammatory cytokines through AP-1 42 and/or NF-kB 43 and with its prolonged activation promotes cell death (necrosis and/or apoptosis) depending on cell type and stimulus and may have both pro-or anti-apoptotic effects in hepatocytes.…”

Primary human muscle precursor cells obtained from young and old donors produce similar proliferative, differentiation and senescent profiles in culture

“…We also examined the secretion of the regulatory cytokine TGF-b1 during differentiation and the ability of young and old cells to respond to, and recover from, TGF-b1 treatment during differentiation. TGF-b1 is a key myogenic regulatory cytokine and studies suggest that its expression may be altered with age (Zentella & Massague, 1992;Carlson et al, 2009a). No significant difference in any of the parameters was observed between young and old donors.…”

“…TGF-b1 production in early passage and senescent cells TGF-b1 is an important cytokine involved in regulating skeletal muscle myogenesis (Zentella & Massague, 1992;Carlson et al, 2009a). The ability of TGF-b1 to inhibit myoblast differentiation and to depress proliferation has been documented (Massague et al, 1986;Allen & Boxhorn, 1987;Greene & Allen, 1991).…”

The Making of Pancreatic β Cells: Advances and Apprehensions

“…Similar studies were conducted in various organs such as Muscle [148], Skin [149] and Neuronal cells [150]. Heterochronic and isochronic transplant studies [151] have shown the increased proliferation rates of old islet β cells which were transplanted to young mice and of young islet β cells which were transplanted to young mice.…”