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

Research output: Contribution to journalArticlepeer-review

M.F.P. Silvestre, B. Viollet, P. W. Caton, J. Leclerc, I. Sakakibara, M. Foretz, M.C. Holness, M.C. Sugden

Original languageEnglish
Pages (from-to)55-60
JournalLife Sciences
Early online date13 Feb 2014
Accepted/In press27 Jan 2014
E-pub ahead of print13 Feb 2014
Published28 Mar 2014

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Abstract

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 AMPKα1/2 knockout mice (AMPKα1/2−/−) fed ad libitum (AL) or a 30% calorie restricted (CR) diet and L6 rat myoblasts incubated with SIRT1 inhibitor (EX527).Key findingsCR-AMPKα1/2−/− displayed impaired glucose tolerance (*p < 0.05), in association with down-regulated SIRT1 and PGC-1α expression (< 300% vs. CR-WT, ±±p < 0.01). Moreover, AMPK activity was decreased following SIRT1 inhibition in L6 cells (~ 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.

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