The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions

Aims: SIRT1 and AMP-activated protein kinase (AMPK) share common activators, actions and target molecules. Previous studies have suggested that a putative SIRT1-AMPK regulatory network could act as the prime initial sensor for calorie restriction-induced adaptations in skeletal muscle-the major site of insulin-stimulated glucose disposal. Our study aimed to investigate whether a feedback loop exists between AMPK and SIRT1 in skeletal muscle and how this may be involved glucose tolerance. Main methods: To investigate this, we used skeletal muscle-specific AMPK alpha 1/2 knockout mice (AMPK alpha l/2(-/-)) fed ad libitum (AL) or a 30% calorie restricted (CR) diet and L6 rat myoblasts incubated with SIRT1 inhibitor (EX527). Key findings: CR-AMPK alpha 1/2(-/-) displayed impaired glucose tolerance (*p<0.05), in association with downregulated SIRT1 and PGC-l alpha expression (<300% vs. CR-WT,(+/-+/-)p<0.01). Moreover, AMPK activity was decreased following SIRT1 inhibition in L6 cells (similar to 0.5-fold vs. control, *p<0.05). Significance: This study demonstrates that skeletal muscle-specific AMPK deficiency impairs the beneficial effects of CR on glucose tolerance and that these effects may be dependent on reduced SIRT1 levels. (C) 2014 Elsevier Inc. All rights reserved.