Skip to main content
ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #307314
Title: Skeletal muscle Sirt3 expression and mitochondrial respiration are regulated by a prenatal low protein diet

Author
item Larson, Kate
item Roemmich, James
item JOHNSON, LUANN - University Of North Dakota
item Dekrey, Emilie
item JOHNSON, W - Retired ARS Employee

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2014
Publication Date: 2/2/2015
Publication URL: http://handle.nal.usda.gov/10113/60643
Citation: Claycombe, K.J., Roemmich, J.N., Johnson, L., Dekrey, E.E., Johnson, W.T. 2015. Skeletal muscle Sirt3 expression and mitochondrial respiration are regulated by a prenatal low protein diet. Journal of Nutritional Biochemistry. 26(2):184-189.

Interpretive Summary: Obesity and obesity-associated chronic diseases such as type 2 diabetes (T2D) are linked to abnormal skeletal muscle energy metabolism stemming from alterations in the function of intracellular organelles called mitochondria. A specific protein called sirtuin protein 3 (Sirt3) found in skeletal muscles contributes to development of T2D by reducing mitochondrial energy metabolism. Other proteins such succinate dehydrogenase (SDH) regulate mitochondrial energy metabolism when their protein structure is chemically modified (e.g. acetylation or addition of acetyl group). When acetylated, SDH protein is inactive, which slows mitochondrial energy metabolism. Using rat model, we found that maternal low-protein and postnatal high-fat diets may increase the risk for T2D by decreasing skeletal muscle energy metabolism by increasing Sirt3 which in turn decreases the amounts of the active form of SDH enzyme.

Technical Abstract: 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 diet would increase T2DM risk due Sirt3 dysfunction within skeletal muscle mitochondria. Using our maternal LP and postnatal HF diet model, we showed that skeletal muscle mitochondrial oxygen consumption rate (OCR) was decreased by maternal LP diet. Mitochondria copy number, mitochondrial thermogenesis (UCP-1) expression, and mitochondrial biogenic factors including nuclear respiratory factor 1 (NRF1) and cytochrome c oxidase 1 and 4 (COX-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 decreased by maternal LP diet (P=0.07). 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.