Skeletal muscle Sirt3 expression and mitochondrial respiration are regulated by a prenatal low-protein diet

J Nutr Biochem. 2015 Feb;26(2):184-9. doi: 10.1016/j.jnutbio.2014.10.003. Epub 2014 Nov 14.


Malnutrition during the fetal growth period increases risk for later obesity and type 2 diabetes mellitus (T2DM). We have shown that a prenatal low-protein (8% protein; LP) diet followed by postnatal high-fat (45% fat; HF) diet results in offspring propensity for adipose tissue catch-up growth, obesity and T2DM in Sprague-Dawley rats. Skeletal muscle is the major tissue for insulin-mediated glucose uptake. Dysfunctional skeletal muscle mitochondrial function, particularly reduction in expression of mitochondrial protein sirtuin protein 3 (Sirt3) contributes to development of T2DM by reducing mitochondrial respiration. Therefore, we hypothesized that maternal LP and postnatal HF diets would increase T2DM risk due to Sirt3 dysfunction within skeletal muscle mitochondria. Using our maternal LP and postnatal HF diet model, we showed that skeletal muscle mitochondrial oxygen consumption rate was decreased by maternal LP diet. Mitochondria copy number, mitochondrial thermogenesis (UCP-1) expression and mitochondrial biogenic factors including nuclear respiratory factor 1 and cytochrome c oxidases 1 and 4 were unaffected by maternal LP and postnatal HF diets. Skeletal muscle Sirt3 mRNA decreased with maternal LP diet. A mitochondrial substrate of Sirt3, succinate dehydrogenase (SDH), is regulated by Sirt3 via lysine residue acetylation status of SDH. Acetylated SDH protein (inactive form) levels were moderately decreased by maternal LP diet. Taken together, these data suggest that maternal LP and postnatal HF diets may increase the risk for T2D by decreasing skeletal muscle oxidative respiration via increased Sirt3 and possibly by decreased amounts of the active form of SDH enzyme.

Keywords: Maternal low-protein diet; Mitochondria; SDH; SIRT3; Skeletal muscle respiration.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • Animals, Newborn
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat / adverse effects
  • Diet, Protein-Restricted / adverse effects*
  • Disease Susceptibility
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Developmental*
  • Male
  • Maternal Nutritional Physiological Phenomena*
  • Mitochondria, Muscle / enzymology
  • Mitochondria, Muscle / metabolism*
  • Mitochondria, Muscle / pathology
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Pregnancy
  • Protein Processing, Post-Translational
  • Protein Subunits / metabolism
  • Rats, Sprague-Dawley
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism*
  • Succinate Dehydrogenase / metabolism*


  • Protein Subunits
  • Succinate Dehydrogenase
  • Sirtuin 3