Succinate promotes skeletal muscle protein synthesis via Erk1/2 signaling pathway

Mol Med Rep. 2017 Nov;16(5):7361-7366. doi: 10.3892/mmr.2017.7554. Epub 2017 Sep 20.


It is well known that endurance training is effective to attenuate skeletal muscle atrophy. Succinate is a typical TCA metabolite, of which exercise could dramatically increase the content. The present study aimed to investigate the effect of succinate on protein synthesis in skeletal muscle, and try to delineate the underlying mechanism. The in vitro study revealed that succinate dose‑dependently increased protein synthesis in C2C12 myotube along with the enhancement of phosphorylation levels of AKT Serine/Threonine Kinase 1(Akt), mammalian target of rapamycin, S6, eukaryotic translation initiation factor 4E, 4E binding protein 1 and forkhead box O (FoxO) 3a. Furthermore, it was demonstrated that 20 mM succinate markedly increased [Ca2+]i. Then, the phospho‑extracellular regulated kinase (Erk), ‑Akt level and the crosstalk between Erk and Akt were elevated in response to succinate. Notably, the Erk antagonist (U0126) or mTOR inhibitor (rapamycin) abolished the effect of succinate on protein synthesis. The in vivo study verified that succinate dose‑dependently increased the protein synthesis, in addition to phosphorylation levels of Erk, Akt and FoxO3a in gastrocnemius muscle. In summary, these findings demonstrated that succinate promoted skeletal muscle protein deposition via Erk/Akt signaling pathway.

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Calcium / analysis
  • Cell Line
  • Forkhead Transcription Factors / metabolism
  • Immunoprecipitation
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Nitriles / pharmacology
  • Protein Biosynthesis / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sirolimus / pharmacology
  • Succinic Acid / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism


  • Butadienes
  • Forkhead Transcription Factors
  • Nitriles
  • U 0126
  • Succinic Acid
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Calcium
  • Sirolimus