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The E3 ubiquitin ligase TRAF6 intercedes in starvation-induced skeletal muscle atrophy through multiple mechanisms

Pradyut K Paul1, Shephali Bhatnagar, Vivek Mishra

  • 1Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.

Molecular and Cellular Biology
|February 1, 2012
PubMed

Insights

Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a key role in muscle loss during starvation. Inhibiting TRAF6 reduces muscle atrophy by impacting key regulatory proteins and pathways.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Physiology

Background:

  • Starvation causes skeletal muscle mass loss through fiber atrophy.
  • Distinct pathways contribute to starvation-induced muscle atrophy, with some mechanisms remaining unclear.
  • Understanding these unique atrophic programs is crucial for metabolic and physiological research.

Purpose of the Study:

  • To investigate the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in starvation-induced muscle atrophy.
  • To elucidate the molecular mechanisms by which TRAF6 regulates skeletal muscle catabolism during nutrient deprivation.
  • To explore the involvement of endoplasmic reticulum stress and unfolding protein response in this process.

Main Methods:

  • Targeted ablation of TRAF6 in skeletal muscle.
  • Analysis of key atrophy regulators (e.g., MAFBx, MuRF1, LC3B, Beclin1).
  • Assessment of signaling pathways including Akt, FoxO3a, and AMPK.
  • Investigation of endoplasmic reticulum stress and unfolding protein response markers.
  • Examination of TRAF6 ubiquitination status.

Main Results:

  • TRAF6 ablation suppressed the expression of atrophy regulators (MAFBx, MuRF1, p62, LC3B, Beclin1, Atg12, Fn14).
  • TRAF6 deficiency improved Akt and FoxO3a phosphorylation and inhibited AMPK activation during starvation.
  • Endoplasmic reticulum stress and unfolding protein response pathways were implicated in starvation-induced muscle atrophy.
  • Lysine 63-linked autoubiquitination of TRAF6 was identified as essential for its function in muscle atrophy.

Conclusions:

  • TRAF6 is a critical regulator of starvation-induced skeletal muscle atrophy.
  • TRAF6 influences key atrophy pathways and signaling cascades, including ER stress.
  • Lysine 63-linked autoubiquitination of TRAF6 is vital for its role in muscle catabolism.

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