Thbs1 regulates skeletal muscle mass in a TGFß-Smad2/3-ATF4-dependent manner.
Cell Rep
; 43(5): 114149, 2024 May 28.
Article
in En
| MEDLINE
| ID: mdl-38678560
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 ß (TGFß)-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 TGFß-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 TGFß-Smad3-ATF4 signaling. Thus, Thbs1-mediated TGFß-Smad3-ATF4 signaling in skeletal muscle regulates tissue rarefaction, suggesting a target for atrophy-based muscle diseases and sarcopenia with aging.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Muscular Atrophy
/
Signal Transduction
/
Transforming Growth Factor beta
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Muscle, Skeletal
/
Thrombospondin 1
/
Smad2 Protein
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Smad3 Protein
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Activating Transcription Factor 4
Limits:
Animals
Language:
En
Journal:
Cell Rep
Year:
2024
Type:
Article
Affiliation country:
United States