Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner

Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 or the Atf4 gene antagonizes Thbs1-induced muscle atrophy. More importantly, Thbs1−/− mice show significantly reduced levels of denervation- and caloric restriction-mediated muscle atrophy, along with blunted TGFβ-Smad3-ATF4 signaling. Thus, Thbs1-mediated TGFβ-Smad3-ATF4 signaling in skeletal muscle regulates tissue rarefaction, suggesting a target for atrophy-based muscle diseases and sarcopenia with aging. [Display omitted] •Thbs1 expression is induced in skeletal muscle under conditions causing atrophy•Thbs1 overexpression induces profound skeletal muscle atrophy•Thbs1-induced skeletal muscle atrophy is through TGFβ-Smad2/3 signaling•Thbs1-null mice are resistant to denervation- and starvation-induced muscle atrophy Vanhoutte et al. show that Thbs1 is induced with skeletal muscle atrophy and that Thbs1 directly incites skeletal muscle wasting by modulating autophagy and ubiquitin-proteosome activity. Thbs1-null mice are partially protected from denervation- and starvation-induced muscle atrophy. Mechanistically, Thbs1 facilitates TGFβ-Smad2/3 signaling and ATF4 expression to mediate muscle atrophy.