{Reference Type}: Journal Article
{Title}: Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner.
{Author}: Vanhoutte D;Schips TG;Minerath RA;Huo J;Kavuri NSS;Prasad V;Lin SC;Bround MJ;Sargent MA;Adams CM;Molkentin JD;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 5
{Year}: 2024 May 28
暂无{DOI}: 10.1016/j.celrep.2024.114149
{Abstract}: 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.