title: Translating the effects of dietary flavonoids on energy metabolism into physical activity benefits
Creators: name: Sadler, D
Publisher: name: Liverpool John Moores University
Year: 2021

description: Introduction: Exercise tolerance gradually declines with sedentary ageing, which contributes to reduced quality of life. With ageing, slower pulmonary oxygen uptake kinetics manifest as a consequence of impairments along the oxygen transport and utilisation pathways. Consequently, there is a mismatch between metabolic demand and O2 delivery, and the oxygen deficit is exacerbated during exercise. Strategies that target the vascular endothelium and skeletal muscle are therefore required to respectively improve O2 delivery and utilisation. Flavonoids may provide therapeutic value through their interaction with cellular processes associated with energy metabolism, but their exact effects on vascular endothelial and skeletal muscle cells are yet to be fully described. Objective: The overall objective of this thesis is to investigate whether flavonoid supplementation impacts V̇O2 kinetics and exercise tolerance in vivo, and to examine whether flavonoids modulate vascular endothelial and/or skeletal muscle cell (control and aged) function as it relates to energy metabolism, in vitro. Methods: Three models were used to achieve the thesis objectives: 1) Randomised, double-blind placebo-controlled trial to investigate whether flavonoid supplementation modulates V̇O2 kinetics and exercise tolerance in physically inactive middle-aged adults. 2) human vascular endothelial cell model to investigate the effects of flavonoids on RONS production, mitochondrial function and cells signalling. 3) Replicative ageing skeletal myoblast/myotube model to investigate the impact of ageing on the effects of micromolar concentrations of flavonoids on RONS production, mitochondrial function, cell signalling and metabolic signatures. Results: Model 1: Cocoa-flavanol supplementation sped phase II V̇O2 kinetics by 15% during moderate-intensity exercise in physically inactive middle-aged adults, but did not alter exercise tolerance. Model 2: In vascular endothelial cells, antimycin A augmented ROS emission, which was modulated by flavonoids in a dose-dependent manner. However, flavonoids did not impact mitochondrial respiration. EPI treatment augmented NRF2 expression and genes associated with mitochondrial remodelling. NRF2 induction in vascular endothelial cells appeared downstream of increased ERK1/2 signalling and may relate to increased NO bioavailability. Model 3: Ageing attenuated coupling efficiency and OXPHOS in myotubes, but not myoblasts, whilst increasing mitochondrial ROS production. Flavonoid treatment did not rescue age-related mitochondrial dysfunction. However, flavonoids upregulated NRF2 in skeletal muscle cells, and in the presence of EPI, NRF2 induction appeared downstream of increased AMPK signalling, but independent of NO bioavailability. Replicative ageing significantly altered the metabolic signatures of myoblasts and myotubes, which were only partially affected by flavonoid treatment. Conclusion(s): Cocoa-flavanols speed V̇O2 kinetics during moderate intensity exercise, but do not enhance exercise tolerance. The speeding of V̇O2 kinetics with cocoa flavanols in vivo may relate to the action of flavonoids on vascular endothelial and skeletal muscle cellular processes. Flavonoids differentially impact mitochondrial ROS production and gene expression profiles in skeletal muscle and vascular endothelial cells. However, flavonoids do not play a major role in modulating mitochondrial respiration, regardless of cell type. EPI in-particular may afford mitochondrial adaptations via induction of NRF2 and ERK1/2 or AMPK signalling in vascular endothelial and skeletal muscle cells, respectively, potentially through the effects of hormesis. In the context of sedentary ageing, flavonoid supplementation may enhance quality of life through effects on V̇O2 kinetics, and the modulation of RONS production and adaptive responses at the cellular level.