Smart, Thomas
(2024)
Exploring the effects of ageing, cancer, and exercise on skeletal muscle mitochondrial function.
PhD thesis, University of Nottingham.
Abstract
As the worldwide population ages, there becomes a growing prevalence of age associated muscle mass and function, known as sarcopenia. Sarcopenia is well recognised to be associated with poor health outcomes, with reduced life expectancy and worse clinical outcomes well established. The ageing population has also led to an increased prevalence of cancer. Cancer cachexia is the loss of muscle mass and function combined with anorexia caused by malignancy, which is associated with worse clinical outcomes for those undergoing cancer treatment. Given the increasing burden of both sarcopenia and cancer cachexia on worldwide healthcare systems, it is of growing importance to understand the physiology underpinning both conditions. This thesis will explore the role of skeletal muscle mitochondrial oxidative phosphorylation changes in both healthy ageing and in cancer patients.
Skeletal muscle mitochondrial oxidative phosphorylation function is a key function in enabling the supply of energy, in the form of ATP, to skeletal muscle. Given the decline in muscle function seen in both sarcopenia and cachexia, it is theorised that this may be driven by declines in oxidative phosphorylation function.
Chapter 3 explores the changes seen in healthy ageing via the recruitment of healthy young and older volunteers. Within our cohorts we did not witness a difference in oxidative phosphorylation between the two age groups. When exploring the broader literature, there is a growing body of evidence showing that activity levels are important in maintaining mitochondrial oxidative phosphorylation. Due to the importance of physical activity in maintaining skeletal muscle oxidative phosphorylation function, a further main aim of this thesis is to investigate the impact of a 4-week exercise intervention upon this in healthy volunteers and those awaiting surgery for cancer.
This is investigated in healthy volunteers in Chapter 4, where the older participants recruited in Chapter 3 enrolled in a 4-week exercise program. The exercise program was unsupervised and home-based, with participants performing either High-intensity interval training or resistance training.
High intensity interval training has a growing body of evidence showing it can improve cardiorespiratory fitness within a shorter timeframe than traditional moderate intensity continuous training, but it appears unable to alter body composition. Resistance exercise training has traditionally been used to improve body composition, and as is demonstrated in a literature review in Chapter 2 appears able to improve cardiorespiratory fitness in healthy older adults. Hence both exercise modalities were selected to be explored in Chapter 4.
Neither of the exercise programs utilised in Chapter 4 made a significant impact upon functional measurements or skeletal muscle oxidative phosphorylation within a healthy older cohort. This was likely due to both the high baseline of the recruited participants, and the exercise interventions themselves not providing enough stimulation to elicit physiological adaptation.
Chapter 5 investigates the impact of cancer upon these measures. Participants awaiting curative surgery for either prostate or colorectal cancer were recruited from an NHS foundation trust. Due to the study timeframe being during the COVID-19 pandemic, adjustments had to be made to the assessments made but muscle biopsies remained included to allow for skeletal muscle oxidative phosphorylation assessment. Participants were assessed originally 4-weeks prior to their planned operation, where the cancer patient cohort had significantly reduced extrinsic skeletal muscle oxidative phosphorylation at the maximal coupled, and uncoupled state. This is a novel finding within human physiology, with no current publications published regarding this in non-metastatic disease states, and it aligns with the pre-clinical models within the literature.
The exercise interventions utilised in Chapter 4, are then utilized in the cancer cohort of Chapter 5 as a 4-week prehabilitation programme prior to their planned surgical date. Unlike in the healthy cohort, within the cancer cohort the High-intensity interval training appears to improve skeletal muscle maximal uncoupled oxidative phosphorylation.
In summary, this thesis explores the role of skeletal muscle mitochondrial function in healthy ageing and in cancer cachexia. Within both cohorts, it will investigate the impact of high-intensity interval training and resistance exercise training upon skeletal muscle mitochondrial oxidative phosphorylation.
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