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Title: Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-lalpha in skeletal muscle

Author
item PALACIOS, ORSOLYA - Children'S Nutrition Research Center (CNRC)
item CARMONA, JUAN - Harvard Medical School
item MICHAN, SHADAY - Harvard Medical School
item CHEN, KE YUN - Children'S Nutrition Research Center (CNRC)
item MANABE, YASUKO - Harvard Medical School
item WARD III, JACK LEE - Children'S Nutrition Research Center (CNRC)
item GOODYEAR, LAURA - Harvard Medical School
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Aging
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/13/2009
Publication Date: 9/15/2009
Citation: Palacios, O.M., Carmona, J.J., Michan, S., Chen, K.Y., Manabe, Y., Ward III, J., Goodyear, L.J., Tong, Q. 2009. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-l alpha in skeletal muscle. Aging. 1(9):771-783.

Interpretive Summary: SIRT3 is a member of the sirtuin family of protein modification enzymes (deacetylases). Its expression and function in skeletal muscle is not known. In this study, we explore the SIRT3 expression and function in skeletal muscle. We report that SIRT3 is more highly expressed in fat-burning red muscle compared to sugar-burning white muscles. Exercise training increases SIRT3 expression in muscle. Furthermore, we find that SIRT3 protein level in skeletal muscle changes according to diet, for SIRT3 expression is increased by fasting and dietary restriction, yet it is decreased by high-fat diet feeding. In mice deficient of SIRT3, we find that a key metabolic regulatory enzyme, AMPK, is inactivated. The expression of another key metabolic regulatory factor, PGC-1alpha, is also down regulated in muscle. This suggests that SIRT3 is needed to sustain the action of these factors in vivo. Our study for the first time reveals that SIRT3 expression in skeletal muscle responds to exercise and nutritional intakes and the loss of SIRT3 may down-regulate muscle function. These findings establish SIRT3 as a novel metabolic regulator in skeletal muscle.

Technical Abstract: 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.