Mechanisms and nutritional countermeasures to musculoskeletal disuse atrophy

Edwards, Sophie Jacqueline (2022). Mechanisms and nutritional countermeasures to musculoskeletal disuse atrophy. University of Birmingham. Ph.D.

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Abstract

Musculoskeletal disuse negatively impacts muscle mass and physiological functioning. Mechanistically, disuse-induced alterations in muscle mass are underpinned by alterations in myofibrillar protein turnover. However, the implications of disuse on mitochondrial functioning remains to be fully eluded. Accordingly, Chapter 2 explored whether a 7d period of reduced ambulation (<1,500 steps.d\(^{-1}\)) promoted alterations in skeletal muscle oxidative metabolism in young males. We report that 7d of reduced ambulation significantly reduced citrate synthase activity, without altering the abundance of proteins involved in mitochondrial functioning, mitochondrial dynamics, oxidative metabolism or skeletal muscle insulin signalling. Based on the importance of skeletal muscle anabolic sensitivity to prevent disuse induced atrophy, Chapter 3 assessed whether a high-dose leucine supplementation intervention could prevent alterations in fat free mass and strength during a 7d period of lower limb immobilization in young males. Here we report that there was a significant reduction in fat free mass (3.6 ± 0.5%) and strength (27.9 ± 4.4%) following 7d immobilization, with no effect of high-dose leucine supplementation compared with placebo. Mechanistically, disuse induced declines in fat free mass occurred in parallel to impaired MyoPS and mitochondrial protein synthesis (MitoPS) rates in the immobilised leg vs. control leg. Chapter 4 assessed the mechanistic ability of (-)-epicatechin (EPI) and its metabolite hippuric acid (HA) upon muscle morphology and metabolism within an in vitro model of atrophy. Under atrophy like conditions (24h dexamethasone (DEX)) C2C12 myotube diameter was significantly greater following co-incubation with either HA or EPI compared to the vehicle control (VC). Mechanistically, the co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates and partially attenuated proteolysis, preventing DEX-induced alterations in autophagic signalling. In conclusion, this thesis improved our understanding of the mechanisms underpinning disuse-induced muscle atrophy and the effectiveness of two nutritional countermeasures to prevent the negative physiological consequences of musculoskeletal disuse.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):