Shur, Natalie F.
(2024)
The impacts of bed rest and acute trauma on muscle metabolic health in humans.
PhD thesis, University of Nottingham.
Abstract
Physical inactivity is a global public health problem and has significant detrimental health consequences. Periods of physical inactivity or immobilisation are common in clinical populations secondary to injury, illness, disease or advancing age. There are currently substantial gaps in our knowledge of the rate and magnitude of skeletal muscle and metabolic dysregulation during bed rest and trauma. Further insight into the processes underpinning these changes is required to develop effective future countermeasures.
The objective of this thesis was to further the understanding of the underlying mechanisms driving skeletal muscle atrophy, changes in muscle protein turnover and a reduction in whole-body and leg insulin sensitivity in immobilisation and trauma. Three human volunteer studies were conducted during the course of this thesis. The first study aimed to evaluate the change in insulin-stimulated whole-body glucose disposal, muscle glycogen content and fuel oxidation during acute (3 days) and chronic (56 days) bed rest in healthy male participants maintained in energy balance. The reduction in insulin-stimulated whole-body insulin sensitivity was rapid (manifested by 3 days), and a similar magnitude to that observed after chronic bed rest. However chronic bed rest was associated with a shift in fuel oxidation, which could not be explained by changes in intramyocellular lipid (IMCL) content but was reflected by the muscle transcriptional response to chronic bed rest, suggesting differences in underlying mechanisms from the acute to chronic state.
The second study assessed for concurrent changes in leg muscle volume, protein turnover and insulin-stimulated leg glucose uptake and muscle glycogen storage in acute bed rest and subsequent structured remobilisation of 3 days duration. Concurrent reductions in leg glucose uptake (explained by reductions in leg blood flow), and muscle glycogen storage as well as myofibrillar protein synthesis (MPS) and whole-body myofibrillar protein breakdown (MPB) after 3 days of bed rest were apparent. Structured remobilisation (but not ambulation alone) restored bed rest-associated reductions in leg muscle volume and MPS, but not insulin-stimulated leg glucose uptake or muscle glycogen storage after bed rest. This study highlighted divergences in muscle fuel and protein metabolism, as well as the importance of exercise rehabilitation following short duration bed rest.
The final study aimed to evaluate the individual and combined impact of immobilisation and trauma/inflammation on medial gastrocnemius muscle thickness and architecture, cumulative MPS and whole-body MPB in ankle fracture patients and matched healthy volunteers undergoing 2 weeks of unilateral cast immobilisation. Trauma plus immobilisation caused greater declines in medial gastrocnemius muscle thickness compared with immobilisation alone, but similar declines in cumulative MPS over 2 weeks and no difference in whole-body MPB measured at 2 weeks. Trauma was also associated with a profound systemic (pro-inflammatory cytokines) and muscle (mRNA) inflammatory response which was absent in immobilisation alone in the healthy volunteers. Furthermore, a reduction in chronic MPS and muscle thickness was evident in the injured leg, but not the uninjured leg, suggesting a differential impact on muscle of local vs systemic inflammation.
Collectively, the work in this thesis presents novel mechanistic insight into the impact of immobilisation and trauma on skeletal muscle mass and immobilisation on whole-body and limb insulin sensitivity. Namely, that acute and chronic bed rest cause a similar magnitude in decline in whole-body insulin sensitivity, however the underlying mechanisms appear to differ. Secondly, that although acute bed rest causes rapid reductions in muscle mass, protein turnover and leg glucose uptake, there is a mismatch in their restoration after a short period of structured remobilisation. Finally, trauma plus inflammation causes greater declines in muscle thickness compared with immobilisation alone, with similar reductions in MPS, and local inflammation is implicated in muscle mass loss in acute limb trauma. These findings may provide the basis to the development of future potential countermeasures.
| Item Type: |
Thesis (University of Nottingham only)
(PhD)
|
| Supervisors: |
Greenhaff, Paul
Macdonald, Ian |
| Keywords: |
Physical inactivity; Skeletal muscle atrophy; Muscle protein; Insulin sensitivity; Muscle glycogen content |
| Subjects: |
Q Science > QP Physiology |
| Faculties/Schools: |
UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences |
| Item ID: |
76963 |
| Depositing User: |
Shur, Natalie
|
| Date Deposited: |
16 Jul 2024 04:40 |
| Last Modified: |
12 Dec 2024 04:30 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/76963 |
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