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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #304904
Title: Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3

Author
item LIN, LIGEN - Children'S Nutrition Research Center (CNRC)
item CHEN, KEYUN - Children'S Nutrition Research Center (CNRC)
item KHALEK, WAED - Dynamique Musculaire Et Metabolisme (DMEM)
item WARD, JACK - Children'S Nutrition Research Center (CNRC)
item YANG, HENRY - Children'S Nutrition Research Center (CNRC)
item CHABI, BEATRICE - Dynamique Musculaire Et Metabolisme (DMEM)
item WRUTNIAK-CABELLO, CHANTAL - Dynamique Musculaire Et Metabolisme (DMEM)
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2013
Publication Date: 1/15/2014
Citation: Lin, L., Chen, K., Khalek, W.A., Ward, J.L., Yang, H., Chabi, B. 2014. Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3. PLoS One. 9(1):e85636.

Interpretive Summary: SIRT3 is a protein-modification enzyme (deacetylase) that regulates the function of many metabolic enzymes. We have previously found that SIRT3 level is higher in the red muscle than white muscle. Muscle SIRT3 level is also activated by food restriction. To investigate SIRT3 function in muscle, we generated genetically engineered mice with muscle-specific expression of one isoform of SIRT3 (TG mice). We found that the TG mice had increased energy expenditure and lipid oxidation. The TG mice exhibited better treadmill exercise endurance, running 45% further than control animals. Moreover, the TG mice displayed higher proportion of the fat-burning type I oxidative muscle fibers. Surprisingly, TG mice had lower muscle mass, likely through an up-regulation of muscle protein turnover. In summary, these results suggest that SIRT3 regulates the formation of oxidative muscle fiber formation, improves muscle metabolic function, and reduces muscle mass, changes that mimic the effects of food restriction.

Technical Abstract: We have previously reported that the expression of mitochondrial deacetylase SIRT3 is high in the slow oxidative muscle and that the expression of muscle SIRT3 level is increased by dietary restriction or exercise training. To explore the function of SIRT3 in skeletal muscle, we report here the establishment of a transgenic mouse model with muscle-specific expression of the murine SIRT3 short isoform (SIRT3M3). Calorimetry study revealed that the transgenic mice had increased energy expenditure and lower respiratory exchange rate (RER), indicating a shift towards lipid oxidation for fuel usage, compared to control mice. The transgenic mice exhibited better exercise performance on treadmills, running 45% further than control animals. Moreover, the transgenic mice displayed higher proportion of slow oxidative muscle fibers, with increased muscle AMPK activation and PPARd expression, both of which are known regulators promoting type I muscle fiber specification. Surprisingly, transgenic expression of SIRT3M3 reduced muscle mass up to 30%, likely through an up-regulation of FOXO1 transcription factor and its downstream atrophy gene MuRF-1. In summary, these results suggest that SIRT3 regulates the formation of oxidative muscle fiber, improves muscle metabolic function, and reduces muscle mass, changes that mimic the effects of caloric restriction.