Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3.
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 PPARδ 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.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Ligen
L
Lin
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Keyun
K
Chen
INRA, UMR 866-Dynamique Musculaire et Métabolisme, Montpellier, France.
Waed
W
Abdel Khalek
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Jack Lee
JL
Ward
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Henry
H
Yang
INRA, UMR 866-Dynamique Musculaire et Métabolisme, Montpellier, France.
Béatrice
B
Chabi
INRA, UMR 866-Dynamique Musculaire et Métabolisme, Montpellier, France.
Chantal
C
Wrutniak-Cabello
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America ; Department of Medicine and Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
Qiang
Q
Tong
D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D052283:Creatine Kinase, MM Form / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D005082:Physical Exertion; D056566:Sirtuin 3 / Q000502:physiology*; D015854:Up-Regulation
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C525046:Sirt3 protein, mouse; D002950:Citrate (si)-Synthase; D052283:Creatine Kinase, MM Form; D056566:Sirtuin 3