Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle.
SIRT3 is a member of the sirtuin family of NAD(+)-dependent deacetylases, which is localized to the mitochondria and is enriched in kidney, brown adipose tissue, heart, and other metabolically active tissues. We report here that SIRT3 responds dynamically to both exercise and nutritional signals in skeletal muscle to coordinate downstream molecular responses. We show that exercise training increases SIRT3 expression as well as associated CREB phosphorylation and PGC-1alpha up-regulation. Furthermore, we show that SIRT3 is more highly expressed in slow oxidative type I soleus muscle compared to fast type II extensor digitorum longus or gastrocnemius muscles. Additionally, we find that SIRT3 protein levels in skeletal muscle are sensitive to diet, for SIRT3 expression increases by fasting and caloric restriction, yet it is decreased by high-fat diet. Interestingly, the caloric restriction regimen also leads to phospho-activation of AMPK in muscle. Conversely in SIRT3 knockout mice, we find that the phosphorylation of both AMPK and CREB and the expression of PGC-1alpha are down regulated, suggesting that these key cellular factors may be important components of SIRT3-mediated biological signals in vivo.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Orsolya M
OM
Palacios
Juan J
JJ
Carmona
Shaday
S
Michan
Ke Yun
KY
Chen
Yasuko
Y
Manabe
Jack Lee
JL
Ward
Laurie J
LJ
Goodyear
Qiang
Q
Tong
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D002950:Citrate (si)-Synthase / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004032:Diet; D005215:Fasting / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000235:genetics; D010805:Physical Conditioning, Animal / Q000502:physiology*; D012727:Sex Characteristics; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C525046:Sirt3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D002950:Citrate (si)-Synthase; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3