Abstract
Physical exercise elicits physiological metabolic perturbations such as energetic and oxidative stress; however, a diverse range of cellular processes are stimulated in response to combat these challenges and maintain cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a highly conserved enzyme that acts as a metabolic fuel sensor and is central to this adaptive response to exercise. The complexity of AMPK’s role in modulating a range of cellular signalling cascades is well documented, yet aside from its well-characterised regulation by activation loop phosphorylation, AMPK is further subject to a multitude of additional regulatory stimuli. Therefore, in this review we comprehensively outline current knowledge around the post-translational modifications of AMPK, including novel phosphorylation sites, as well as underappreciated roles for ubiquitination, sumoylation, acetylation, methylation and oxidation. We provide insight into the physiological ramifications of these AMPK modifications, which not only affect its activity, but also subcellular localisation, nutrient interactions and protein stability. Lastly, we highlight the current knowledge gaps in this area of AMPK research and provide perspectives on how the field can apply greater rigour to the characterisation of novel AMPK regulatory modifications.
Highlights
Adenosine triphosphate (ATP) is the energy currency of the cell containing energyrich phosphoanhydride bonds that fuel a broad range of biochemical processes such as cellular signalling, protein synthesis, cell division and muscle contraction
AMPK was originally thought to be responsible for augmenting insulin-independent glucose uptake into skeletal muscle during exercise, there is mounting evidence suggesting this is not the case and it instead plays a more pivotal role in post-exercise glucose uptake and subsequent glycogen resynthesis [16,19,20]
It is worth noting that Yoon and colleagues [97] recently found that glucose restriction and repression of mTORC1 signalling occurs via AMPK activation of ULK1 and inhibition of leucyl-tRNA synthetase 1, an enzyme that covalently couples leucine to its cognate tRNA using ATP, signifying an energy conservation process involving upregulation of autophagy, a principal cellular energy harvesting pathway
Summary
Adenosine triphosphate (ATP) is the energy currency of the cell containing energyrich phosphoanhydride bonds that fuel a broad range of biochemical processes such as cellular signalling, protein synthesis, cell division and muscle contraction. While α1β2γ1 and α2β2γ1 complexes, which are not limited to expression in skeletal muscle, are stimulated by more prolonged, endurance-based forms of exercise in red, oxidative (slow twitch/type I) skeletal muscle fibres [18] This isoform-specific coordination of AMPK activation in response to exercise is intriguing, and no studies have investigated the cellular mechanism, it is tempting to speculate that this may be achieved through a diverse range of exercise-induced post translational modifications (PTMs) on the specific AMPK heterotrimers. AMPK was originally thought to be responsible for augmenting insulin-independent glucose uptake into skeletal muscle during exercise, there is mounting evidence suggesting this is not the case and it instead plays a more pivotal role in post-exercise glucose uptake and subsequent glycogen resynthesis [16,19,20] This specific context for AMPK’s role in promoting glucose uptake points to a novel set of exercise stimulated PTMs controlling the time and place of AMPK activation. We focus on the current knowledge of reversible AMPK PTMs and their implications for future investigations
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