PDF(Pubmed)
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.
摘要：
肌肉质量损失是慢性疾病和衰老的特征。这里,我们报道,骨骼肌特异性血小板反应蛋白-1转基因小鼠(Thbs1Tg)有严重的肌肉萎缩,运动能力和过早死亡的年龄依赖性下降.机械上,Thbs1激活转化生长因子β（TGFβ）-Smad2/3信号，它还诱导激活转录因子4（ATF4）的表达，这些表达共同调节自噬-溶酶体途径（ALP）和泛素-蛋白酶体系统（UPS）以促进肌肉萎缩。的确,肌纤维特异性抑制TGFβ受体信号抑制ATF4的诱导，使ALP和UPS正常化，并部分恢复Thbs1Tg小鼠的肌肉质量。同样，Smad2和Smad3或Atf4基因的肌纤维特异性缺失拮抗Thbs1诱导的肌肉萎缩。更重要的是,Thbs1-/-小鼠表现出显著降低的去神经和热量限制介导的肌肉萎缩水平，以及钝化的TGFβ-Smad3-ATF4信号。因此，Thbs1介导的TGFβ-Smad3-ATF4信号在骨骼肌中调节组织稀疏，提示基于萎缩的肌肉疾病和肌肉减少症随着衰老的目标。
