Loughborough University
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An examination of blood flow restriction/occlusion interventions to augment or induce hypoxia-mediated mitohormesis and improve exercise performance

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posted on 2024-04-19, 13:12 authored by Donald Peden

The function and content of skeletal muscle mitochondria are inherently linked to the capacity of an individual to sustain muscular contractions and therefore, perform exercise. This is due to the role of the mitochondria in energy metabolism. The exercise stimulus also acts as a regulatory signal for subsequent mitochondrial and skeletal muscle adaptations, specifically mitochondrial biogenesis. Moreover, consequences of the activation of mitochondrial signalling pathways may result in an acute priming effect for subsequent exercise, through improved mitochondrial function, which may be benefit performance. One of the key homeostatic perturbations caused by exercise that results in the activation mitochondrial signalling pathways is hypoxia, specifically, reductions in muscle oxygen availability. An augmented or additional hypoxic stimulus can increase mitochondrial signalling responses. Consequently, interventions have attempted to manipulate muscle oxygen availability, acutely or chronically, to improve exercise performance. The hypoxic stimulus of exercise can be augmented by manipulating oxygen availability systemically, by reducing the oxygen concentration of inspired air, or locally, by restricting the delivery of oxygen to muscle. This Ph.D. examined the use of current strategies which systemically or locally alter oxygen availability to expose the muscle to hypoxia to determine if this could improve mitochondrial respiratory capacity, and subsequently exercise performance.

The process of inducing perturbations to mitochondrial homeostasis in to activate signalling cascades that result in priming, or adaptation of the mitochondria is known as mitohormesis. This Ph.D. examined if hypoxia-induced mitohormesis can improve mitochondrial respiratory capacity using in-depth exploration of mitochondrial function, permitted through recent developments in the measurement of mitochondrial respiration. Specifically, non-invasive measures of oxygen delivery and extraction were combined with holistic analysis of mitochondrial content and mitochondrial respiratory capacity, measured in situ using high-resolution respirometry in permeabilised human skeletal muscle. The experimental research of this Ph.D. primarily focussed on local manipulation of intramuscular oxygen availability, and how this may influence mitochondrial respiration and exercise performance. The application of local hypoxia can be achieved through ischemic preconditioning (IPC), in an attempt acutely induce skeletal muscle priming or through ‘hormesis’, and as blood flow restriction (BFR) combined with exercise, with the aim of chronically augmenting exercise stimuli that are postulated to increase mitochondrial biogenesis.

The first study investigated the application of IPC, an acute mechanism postulated to improve exercise performance, through a preparatory effect which improves tolerance to a subsequent bout of ischemia. This research found that non-lethal ischemic insults interspersed with reperfusion were capable of inducing mitohormesis. This was demonstrated by a protective effect of IPC, which prevented increases in mitochondrial leak respiration, a marker of mitochondrial dysfunction, during exhaustive exercise. Furthermore, this was concomitant with expedited V̇O2 kinetics, with no changes in deoxyhaemoglobin kinetics. This is indicative of proportional increases in both oxygen delivery and extraction.

The second study further examined the mechanism by which IPC may influence the physiological responses of skeletal muscle in situ, using an experimental model involving repeated bouts of restricted oxygen availability. This study exposed permeabilised muscle fibres to repeated hypoxic insults, within a high-resolution respirometer, interspersed with reoxygenation, prior to analysis of mitochondrial respiratory parameters. This experimental model aimed to mimic the hypoxic insults induced by IPC and isolate this stimulus from additional endothelial stimuli of IPC in human experimental models. This research found no differences in mitochondrial respiration following exposure to the hypoxic stimulus. This may indicate that the stimulus of occlusion and the resultant mitohormesis are complex and multi-faceted, involving signalling processes involve the whole cell, not just the mitochondria. This may include interactions with the endothelial stimuli of IPC, also known to activate signalling pathways which influence both the vasculature and the mitochondria.

The third study applied post-exercise BFR as part of a 6 week sprint-interval training (SIT) protocol, to further induce phenotypic change, compared with SIT alone. The rationale for this response was based in the BFR-induced augmentation of homeostatic perturbations caused by exercise. This study demonstrated that SIT was capable of inducing improvements in mitochondrial biogenesis, specifically mitochondrial respiration. The addition of BFR to SIT augmented mitochondrial biogenesis, with greater increases in mitochondrial content and mitochondrial respiration compared with a matched ‘classic’ SIT control. However, despite the novel finding that SIT combined with BFR can induce phenotypic change, exercise performance increased similarly over time in response to the training stimulus in both conditions.

The fourth study compared the hypoxic stimulus of SIT in normoxia and systemic hypoxia, with/without of BFR. This research aimed to determine if the convective reduction of oxygen availability induced by BFR is comparable to the more well researched stimulus of exposure to systemic hypoxia. Furthermore, this study explored if the combination of BFR with systemic hypoxia could further augment homeostatic perturbations resulting from post-exercise BFR combined with sprint-interval training, without negatively impacting the quality of training. This study demonstrated that systemic hypoxia, BFR and a combination of both increased the hypoxic stimulus of SIT, without any reductions in average exercise intensity across the session. Additionally, the BFR interventions increased the deoxygenation status of the microvasculature compared with hypoxia alone.

The main conclusions of this thesis are that blood flow occlusion, used acutely as IPC or post-exercise in combination with SIT, is an effective means of inducing or augmenting skeletal muscle hypoxia. This stimulus of blood flow occlusion and the resultant, non-lethal homeostatic perturbations result in mitohormesis. In the case of IPC, this mitohormesis results in acute mitochondrial priming. In the case of SIT combined with post-exercise BFR, the repeated mitohormesis results in augmented mitochondrial biogenesis. Furthermore, the homeostatic perturbations resulting from BFR are evidenced to be similar, or perhaps more potent, than training combined with exposure to systemic altitude. These adaptive responses extend the literature which has previously demonstrated the activation of mitochondrial signalling pathways in response to blood flow occlusion, to demonstrate improvements in mitochondrial respiration in both acute and chronic applications.



  • Sport, Exercise and Health Sciences


Loughborough University

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© Donald L. Peden

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University.


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Richard Ferguson ; Stephen Bailey

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  • PhD

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  • Doctoral

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