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

Davy Vanhoutte1, Tobias G Schips1, Rachel A Minerath1

  • 1Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Cell Reports
|April 28, 2024
PubMed

Insights

Thrombospondin-1 (Thbs1) activates TGFβ-Smad3-ATF4 signaling, causing muscle atrophy. Inhibiting this pathway partially restores muscle mass, suggesting a therapeutic target for muscle wasting diseases and aging-related sarcopenia.

Area of Science:

  • Muscle physiology and molecular biology
  • Aging research
  • Cellular signaling pathways

Background:

  • Muscle mass loss is common in chronic illness and aging.
  • Skeletal muscle atrophy impacts exercise capacity and survival.
  • Identifying molecular drivers of muscle atrophy is crucial.

Purpose of the Study:

  • To investigate the role of thrombospondin-1 (Thbs1) in skeletal muscle atrophy.
  • To elucidate the molecular mechanisms linking Thbs1 to muscle wasting.
  • To explore Thbs1-mediated signaling as a therapeutic target for muscle atrophy.

Main Methods:

  • Utilized skeletal muscle-specific Thbs1 transgenic (Thbs1 Tg) and knockout (Thbs1-/-) mouse models.
  • Investigated the involvement of transforming growth factor β (TGFβ)-Smad2/3 signaling and activating transcription factor 4 (ATF4).
  • Assessed the modulation of the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS).

Main Results:

  • Thbs1 Tg mice exhibited significant muscle atrophy, reduced exercise capacity, and premature death.
  • Thbs1 activates TGFβ-Smad2/3 signaling, leading to ATF4 induction, which modulates ALP and UPS, causing atrophy.
  • Inhibition of TGFβ-receptor signaling or deletion of Smad2/3 or Atf4 partially rescued muscle mass in Thbs1 Tg mice.
  • Thbs1-/- mice showed reduced atrophy in denervation and caloric restriction models, with blunted TGFβ-Smad3-ATF4 signaling.

Conclusions:

  • Thbs1-mediated TGFβ-Smad3-ATF4 signaling in skeletal muscle drives tissue rarefaction and atrophy.
  • This pathway is a key regulator of muscle mass maintenance.
  • Targeting Thbs1-mediated signaling offers a potential therapeutic strategy for muscle atrophy-associated diseases and sarcopenia.
Keywords:
ATF4CP: MetabolismTGFβatrophyautophagyextracellular matrixproteasomeskeletal musclethrombospondin

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