Expression and activation of the 5'AMP-activated protein kinase (AMPK) in exercising and energy-depleted cells: an investigation into the molecular basis underpinning exercise-induced immunosuppression
Moir, Hannah Jayne
University of Wales
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High-intensity exercise has been associated with an increased susceptibility to illness and infections, yet the underlying metabolic mechanism underpinning the onset of a suppressed immune system has yet to be determined. In view of the importance of preventing overtraining and the associated impact on health and sporting performance, the aim of the current thesis was to determine the role of 5'AMP-activated Protein Kinase (AMPK) in the maintenance of cellular energy within immune cells, and thus its influence on the functional abilities of immune cells. Two experimental approaches were employed: in vitro studies involving cultured monocytic monomac6 cells to confirm the importance of AMPK in maintaining correct cellular energy status, and in vivo studies to determine the effects of acute bouts of highintensity exercise of ~70% VO2max in various exercise modes (cycling, running and rowing), on AMPK activation within human mononuclear cells, and several markers of global immune function. Also, an 8-week training programme was employed to investigate the chronic effects of high-intensity exercise on mononuclear cell AMPK activation, and markers of global immune function. In vitro data confirmed AMPKα1 isoform expression in monocytes, which is activated by hypoxia-induced decreases in cellular ATP levels (mimicked by in vitro oligomycin treatment) to phosphorylate inducible phosphofructokinase-2, and activate anaerobic glycolysis to replenish cellular energy stores. In contrast, bouts of high intensity exercise (~70% VO2max for 45 minutes) brought about transient dephosphorylation of AMPK for ~1 hour post-exercise, which correlated to transient decreases in immune function (detected as decreased salivary IgA and suppressed cytokine release). Dephosphorylation of AMPK occurred via an AMP:ATP-independent mechanism, and coincided with a decrease in intracellular levels of reactive oxygen species. Importantly, AMPK inactivation lessened in extent in mononuclear cells following an 8-week training programme. In conclusion, these studies detail the potential involvement of AMPK inactivation, and the consequent disruptions in cellular energy homeostasis in mononuclear cells following an acute bout of exercise. Longitudinal data suggests improvements by chronic training adaptations, but in general, propose a role that AMPK inactivation may repress immune cell function.
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