Language
English
Publication Date
5-28-2024
Journal
Cell Reports
DOI
10.1016/j.celrep.2024.114149
PMID
38678560
PMCID
PMC11217783
PubMedCentral® Posted Date
7-2-2024
PubMedCentral® Full Text Version
Author MSS
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.
Keywords
Animals, Male, Mice, Activating Transcription Factor 4, Autophagy, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Skeletal, Muscular Atrophy, Signal Transduction, Smad2 Protein, Smad3 Protein, Thrombospondin 1, Transforming Growth Factor beta
Published Open-Access
yes
Recommended Citation
Vanhoutte, Davy; Schips, Tobias G; Minerath, Rachel A; et al., "Thbs1 Regulates Skeletal Muscle Mass in a TGFβ-Smad2/3-ATF4-Dependent Manner" (2024). Faculty, Staff and Students Publications. 7982.
https://digitalcommons.library.tmc.edu/baylor_docs/7982
Graphical Abstract