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Ethyl pyruvate preserves IGF-I sensitivity toward mTOR substrates and protein synthesis in C2C12 myotubes

Robert A Frost1, Erika Pereyra, Charles H Lang

  • 1Department of Cellular and Molecular Physiology (H166), Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA. rfrost@psu.edu

Endocrinology
|November 26, 2010
PubMed

Insights

Bacterial infection impairs muscle protein synthesis by inhibiting mTOR signaling. Lipophilic pyruvate derivatives and antioxidants can restore mTOR activity and muscle protein synthesis by maintaining IGF-I sensitivity.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • Bacterial infections disrupt skeletal muscle protein synthesis by inhibiting the mammalian target of rapamycin (mTOR) pathway.
  • Understanding the precise mechanisms of mTOR inhibition is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate how bacterial endotoxins and cytokines inhibit mTOR signaling in muscle cells.
  • To determine if lipophilic pyruvate derivatives can restore mTOR signaling and protein synthesis.

Main Methods:

  • C2C12 myotubes were treated with lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) to mimic bacterial infection effects.
  • Assessed mTOR signaling by measuring phosphorylation of key substrates like S6 kinase-1 and 4E-binding protein-1.
  • Evaluated the impact of methyl pyruvate, ethyl pyruvate, and antioxidants on mTOR activity and insulin-like growth factor-I (IGF-I) sensitivity.

Main Results:

  • LPS/IFN-γ treatment significantly reduced protein synthesis and mTOR signaling, affecting both translation initiation and elongation.
  • Ethyl and methyl pyruvate partially protected against mTOR inhibition, with ethyl pyruvate showing a more pronounced effect.
  • Prolonged LPS/IFN-γ exposure induced IGF-I resistance at the mTOR level, which was reversed by ethyl pyruvate and antioxidants.
  • Antioxidants like N-acetyl cysteine and ascorbic acid also preserved mTOR activity and IGF-I sensitivity.

Conclusions:

  • Bacterial infection components (LPS/IFN-γ) inhibit mTOR signaling and induce IGF-I resistance in skeletal muscle cells.
  • Lipophilic pyruvate derivatives, particularly ethyl pyruvate, and antioxidants show potential in restoring mTOR activity and protein synthesis by maintaining IGF-I sensitivity.

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