Acute Activation of AMP-Activated Protein Kinase Prevents H2O2-Induced Premature Senescence in Primary Human Keratinocytes

We investigated the effects of AMPK on H2O2-induced premature senescence in primary human keratinocytes. Incubation with 50 µM H2O2 for 2 h resulted in premature senescence with characteristic increases in senescence-associated ß-galactosidase (SA-gal) staining 3 days later and no changes in AMPK or p38 MAPK activity. The increase in SA-gal staining was preceded by increases in both p53 phosphorylation (S15) (1 h) and transactivation (6 h) and the abundance of the cyclin inhibitor p21CIP1 (16 h). Incubation with AICAR or resveratrol, both of which activated AMPK, prevented the H2O2-induced increases in both SA-Gal staining and p21 abundance. In addition, AICAR diminished the increase in p53 transactivation. The decreases in SA-Gal expression induced by resveratrol and AICAR were prevented by the pharmacological AMPK inhibitor Compound C, expression of a DN-AMPK or AMPK knock-down with shRNA. Likewise, both knockdown of AMPK and expression of DN-AMPK were sufficient to induce senescence, even in the absence of exogenous H2O2. As reported by others, we found that AMPK activation by itself increased p53 phosphorylation at S15 in embryonic fibroblasts (MEF), whereas under the same conditions it decreased p53 phosphorylation in the keratinocytes, human aortic endothelial cells, and human HT1080 fibrosarcoma cells. In conclusion, the results indicate that H2O2 at low concentrations causes premature senescence in human keratinocytes by activating p53-p21CIP1 signaling and that these effects can be prevented by acute AMPK activation and enhanced by AMPK downregulation. They also suggest that this action of AMPK may be cell or context-specific

Snowmass Theory Frontier Report

This report summarizes the recent progress and promising future directions in theoretical high-energy physics (HEP) identified within the Theory Frontier of the 2021 Snowmass Process.Comment: Contribution to the US Community Study on the Future of Particle Physics (Snowmass 2021), v2: fixed typo

AMPK and the biochemistry of exercise: implications for human health and disease

AMP-activated protein kinase (AMPK) is a phylogenetically conserved fuel-sensing enzyme that is present in all mammalian cells. During exercise, it is activated in skeletal muscle in humans, and at least in rodents, also in adipose tissue, liver and perhaps other organs by events that increase the AMP/ATP ratio. When activated AMPK stimulates energy generating processes such as glucose uptake and fatty acid oxidation and decreases energy consuming processes such as protein and lipid synthesis. Exercise is perhaps the most powerful physiological activator of AMPK and a unique model for studying its many physiological roles. In addition, it improves the metabolic status of rodents with a metabolic syndrome phenotype, as does treatment with AMPK activating agents; therefore, it is tempting to attribute the therapeutic benefits of regular physical activity to activation of AMPK. Here we review the acute and chronic effects of exercise on AMPK activity in skeletal muscle and other tissues. We also discuss the potential role of AMPK activation in mediating the prevention and treatment by exercise of specific disorders associated with the metabolic syndrome including type 2 diabetes and Alzheimer’s disease

AMP-activated protein kinase and its regulation by adiponectin and interleukin-6

Abstract AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that responds to decreases in cellular energy state by activating processes that generate adenosine triphosphate (ATP) (e.g. fatty acid oxidation), and inhibiting others that consume ATP but are not acutely necessary for survival (e.g. fatty acid, triglyceride and protein synthesis). In contrast, sustained decreases in AMPK or a failure to activate it appropriately have been implicated in the pathogenesis of the metabolic syndrome. Recent studies suggest that various hormones can activate or inhibit AMPK. One of these hormones, adiponectin (Adn), an adipokine released by the fat cell, activates AMPK in liver, muscle, primary rat adipocytes, cultured endothelium and almost certainly other cells. Low plasma levels of Adn are associated with the metabolic syndrome; thus, in both humans and experimental animals, they are often accompanied by obesity, insulin resistance, ectopic lipid deposition, and a predisposition to both type 2 diabetes and atherosclerotic heart disease. Recent studies suggest that thiazoledinediones (TZDs), agents used to treat diabetes because they diminish insulin resistance, exert this effect in great measure by increasing the synthesis and release of adiponectin by the adipocyte and secondarily increasing AMPK activity in the liver and other tissues. Another cytokine that has been shown to activate AMPK is interleukin-6 (IL-6). Studies in IL-6 knockout (KO) mice have revealed that AMPK activity is diminished in their muscle and adipose tissue at 3 months of age and that, like the adiponectin KO mice, they are predisposed to obesity, glucose intolerance and hypertriglyceridemia. Likewise, when bred on an Apo E Á / Á they develop more severe atherosclerosis than control mice. Whether AMPK activation by other means prevents the development of the metabolic syndrome in the IL-6 or adiponectin KO mice remains to be determined