Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 313, Issue 4, Pages E493-E505Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00122.2017
Keywords
sirtuin-6; glucose homeostasis; insulin sensitivity; exercise capacity; diabetes; 5'-adenosine monophosphate-activated protein kinase
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Funding
- National Natural Science Foundation of China [81471049, 81670749, 81570518, 81370877]
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Because of the mass and functions in metabolism, skeletal muscle is one of the major organs regulating whole body metabolic homeostasis. SIRT6, a histone deacetylase, has been shown to regulate metabolism in liver and brain; however, its specific role in skeletal muscle is undetermined. In the present study we explored physiological function of SIRT6 in muscle. We generated a muscle-specific SIRT6 knockout mouse model. The mice with SIRT6 deficiency in muscle displayed impaired glucose homeostasis and insulin sensitivity, attenuated whole body energy expenditure, and weakened exercise performance. Mechanistically, deletion of SIRT6 in muscle decreased expression of genes involved in glucose and lipid uptake, fatty acid oxidation, and mitochondrial oxidative phosphorylation in muscle cells because of the reduced AMP-activated protein kinase (AMPK) activity. In contrast, overexpression of SIRT6 in C2C12 myotubes activates AMPK. Our results from both gain- and loss-of-function experiments identify SIRT6 as a physiological regulator of muscle mitochondrial function. These findings indicate that SIRT6 is a potential therapeutic target for treatment of type 2 diabetes mellitus.
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