Interdependence of AMPK and SIRT1 for Metabolic Adaptation to Fasting and Exercise in Skeletal Muscle

Abstract

During fasting and after exercise, skeletal muscle efficiently switches from carbohydrate to lipid as the main energy source to preserve glycogen stores and blood glucose levels for glucose-dependent tissues. Skeletal muscle cells sense this limitation in glucose availability and transform this information into transcriptional and metabolic adaptations. Here we demonstrate that AMPK acts as the prime initial sensor that translates this information into SIRT1-dependent deacetylation of the transcriptional regulators PGC-1α and FOXO1, culminating in the transcriptional modulation of mitochondrial and lipid utilization genes. Deficient AMPK activity compromises SIRT1-dependent responses to exercise and fasting, resulting in impaired PGC-1α deacetylation and blunted induction of mitochondrial gene expression. Thus, we conclude that AMPK acts as the primordial trigger for fasting- and exercise-induced adaptations in skeletal muscle and that activation of SIRT1 and its downstream signalling pathways are improperly triggered in AMPK deficient states.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Resveratrol found in red grape skin is a potent antioxidant that has been shown to reduce amyloid plaque burden and improve memory deficits in transgenic AD mouse models [132,133]. Resveratrol activates the 5'adenosine monophosphate-activated protein kinase pathway, and stimulates activity of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 [134,135], which subsequently activates the PGC1α metabolic regulatory pathway and promotes mitochondrial biogenesis [136][137][138][139]. Several clinical trials are currently underway to investigate the efficacy of resveratrol, including a Phase II trial on mild-to-moderate AD (ClinicalTrials.gov identifier: NCT01504854), a Phase III on mild-to-moderate AD (ClinicalTrials.gov identifier: NCT00743743), and a Phase IV on MCI, which combines resveratrol with omega-3 (ClinicalTrials.gov identifier: NCT01219244).…”

“…Latrepirdine is proposed to interact with glutamate Reduces oxidative stress, reduces amyloid plaques, improves memory deficits in transgenic mouse models of AD No major effect on cognitive function [132][133][134][135][136][137][138][139] AD = Alzheimer's disease; ROS = reactive oxygen species; SOD = superoxide dismutase; MitoQ = mitoquinone mesylate; AMPK = adenosine monophosphate-activated protein kinase; NAD = nicotinamide adenine dinucleotide; SIRT1 = sirtuin 1 receptors, block voltage-dependent calcium channels, and inhibit mitochondrial permeability, thereby suppressing unnecessary mitophagy or apoptosis [153,154]. In a Phase II clinical trial in patients with moderate AD, it significantly improved cognitive function over placebo [155].…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…On a molecular level, a close connection exists between AMPK and the histone/protein deacetylase SIRT1, a molecule supposed to be involved in the genetic changes that mediate the increase in longevity induced by caloric restriction (Canto et al 2010). AMPK and SIRT1 apparently regulate each other and share common target molecules.…”

“…AMPK and SIRT1 apparently regulate each other and share common target molecules. AMPK could be upstream of SIRT1, that is, regulate SIRT1 activity (Canto et al 2010;Um et al 2010), thus controlling SIRT1-mediated effects on aging and health. In addition, due to its interaction with cryptochrome 1, a component of circadian clock in peripheral tissues, AMPK contributes to metabolic entrainment of peripheral clocks (Lamia et al 2009).…”

“…Muscle AMPK is involved in the coordinated transcription of genes important for lipid and glucose metabolism during exercise and for acute control of metabolic fluxes, namely the switch from carbohydrate to lipid oxidation (Hardie 2008;Zhang et al 2009;McGee and Hargreaves 2010;Canto et al 2010;Viollet et al 2009). Thus, AMPK is activated by muscle contraction, which depletes ATP leading to an increase in the AMP/ATP ratio.…”