Mitochondrial complex I deficiency enhances skeletal myogenesis but impairs insulin signaling through SIRT1 inactivation

J Biol Chem. 2014 Jul 18;289(29):20012-25. doi: 10.1074/jbc.M114.560078. Epub 2014 Jun 3.


To address whether mitochondrial biogenesis is essential for skeletal myogenesis, C2C12 myogenesis was investigated after knockdown of NADH dehydrogenase (ubiquintone) flavoprotein 1 (NDUFV1), which is an oxidative phosphorylation complex I subunit that is the first subunit to accept electrons from NADH. The NDUFVI knockdown enhanced C2C12 myogenesis by decreasing the NAD(+)/NADH ratio and subsequently inactivating SIRT1 and SIRT1 activators (pyruvate, SRT1720, and resveratrol) abolished the NDUFV1 knockdown-induced myogenesis enhancement. However, the insulin-elicited activation of insulin receptor β (IRβ) and insulin receptor substrate-1 (IRS-1) was reduced with elevated levels of protein-tyrosine phosphatase 1B after NDUFV1 knockdown in C2C12 myotubes. The NDUFV1 knockdown-induced blockage of insulin signaling was released by protein-tyrosine phosphatase 1B knockdown in C2C12 myotubes, and we found that NDUFV1 or SIRT1 knockdown did not affect mitochondria biogenesis during C2C12 myogenesis. Based on these data, we can conclude that complex I dysfunction-induced SIRT1 inactivation leads to myogenesis enhancement but blocks insulin signaling without affecting mitochondria biogenesis.

Keywords: Insulin Resistance; Mitochondrial Disease; Mitochondrial Metabolism; Myogenesis; Sirtuin 1 (SIRT1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Electron Transport Complex I / antagonists & inhibitors
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism*
  • Gene Knockdown Techniques
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Mice
  • Mitochondrial Diseases / metabolism*
  • Models, Biological
  • Muscle Development / genetics
  • Muscle Development / physiology*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / growth & development*
  • Muscle, Skeletal / metabolism*
  • NAD / metabolism
  • Oxidative Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Sirtuin 1 / antagonists & inhibitors*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism


  • Insulin
  • RNA, Small Interfering
  • NAD
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Electron Transport Complex I
  • NDUFV1 protein, mouse

Supplementary concepts

  • Mitochondrial complex I deficiency