The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise

Abstract

New Findings r What is the topic of this review?The topic of this review is the metabolic effects of AMP-activated protein kinase (AMPK) on glucose and fatty acid (FA) uptake, FA oxidation and mitochondrial biogenesis in skeletal muscle at rest and during exercise/muscle contractions. r What advances does it highlight?This review describes recent studies examining the molecular mechanisms by which AMPK regulates muscle metabolism. It specifically discusses the role of exercise on acetyl-CoA carboxylase and malonyl-CoA in the regulation of FA oxidation. It also discusses the role of AMPK in regulating glucose and FA uptake during exercise. Finally, the review describes the interaction between AMPK, peroxisome proliferator-activated receptor γ co-activator-1α and sirtuin 1 in controlling mitochondrial biogenesis.Insulin resistance is associated with defects in skeletal muscle fatty acid (FA) metabolism that contribute to the development of type 2 diabetes. Endurance exercise increases FA and glucose metabolism, muscle mitochondrial content and insulin sensitivity. In skeletal muscle, basal rates of FA oxidation are dependent on AMP-activated protein kinase (AMPK) phosphorylation of acetyl-CoA carboxylase 2, the rate-limiting enzyme controlling the production of the metabolic intermediate malonyl-CoA. Likewise, AMPK is essential for maintaining muscle mitochondrial content in untrained mice; effects that may be mediated through regulation of the peroxisome proliferator-activated receptor γ co-activator-1α. However, the importance of AMPK in regulating glucose and FA uptake, FA oxidation and mitochondrial biogenesis during and following endurance exercise training is not fully understood. A better understanding of the mechanisms by which endurance exercise regulates substrate utilization and mitochondrial biogenesis may lead to improved therapeutic and preventative strategies for the treatment of insulin resistance and type 2 diabetes.

Plasma and adipose tissue level of angiopoietin-like 7 (ANGPTL7) are increased in obesity and reduced after physical exercise

“…Exercise has been shown to increase the activity of proteins involved in metabolism such as AMPK [62–64] and reduces the expression of inflammation associated proteins such as TNFα [65–67]. For example, we have previously showed that exercise is an important regulator of DNAJB3 protein a member of the HSP40 protein family that has been shown to be downregulated by obesity and upregulated after physical exercise.…”

Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling

“…Incubation of human umbilical vein ECs (HUVECs) with sIL-6Rα/IL-6 trans-signaling complexes for 30 min significantly increased the phosphorylation of STAT3 on Tyr 705 (Fig. 1A), an effect that was significantly inhibited in HUVECs that had been pre-incubated with distinct stimuli that each activate AMPK as determined by assessing ACC1 phosphorylation on Ser 79 (8): AICAR, which is phosphorylated intracellularly to the AMP mimetic ZMP (23); A769662, which binds and activates β1-containing AMPK complexes via an AMP/ADP-independent mechanism (24); and a combination of clinically utilized AMPK activators metformin and salicylate, which synergistically activate AMPK by increasing intracellular AMP concentration and directly binding β1-subunits, respectively (25) (26) (27). Under these conditions, AMPK activation on its own had no detectable effect on the phosphorylation of STAT3.…”

“…An important aspect of this role is the direct phosphorylation of metabolic enzymes such as acetyl coA carboxylase (ACC) 1 and 2, which catalyze the carboxylation of acetyl coA to malonyl-CoA, a key substrate for fatty acid biosynthesis that also inhibits fatty acid transport into mitochondria (7). AMPK-mediated phosphorylation of ACC1 on Ser 79 inhibits its activity thereby suppressing fatty acid synthesis and enhancing β-oxidation (8). An increasing body of evidence has revealed that AMPK is also an important regulator of inflammatory responses.…”

Adipocytes, aldosterone and obesity-related hypertension

“…However, when SW872 cells were treated with the diabetes drug and non-specific AMPK activator metformin, aldosterone secretion was not changed (White, personal communication). AMPK is a key energy regulator activated in low-energy states and is known to stimulate mitochondrial biosynthesis (Marcinko et al 2014). Although the effect described here was initially unexpected, the author suggests it may be reasoned by a direct effect on mitochondrial number and therefore steroid production.…”