The roles of muscle contraction and insulin on restoring glucose uptake with novel pharmaceutical and engineering solutions

不活动和炎症独立地与显著的肌肉萎缩相关，并且当同时存在时，导致与死亡率增加相关的灾难性肌肉质量损失。肌肉质量是通过肌肉蛋白质合成（MPS）和分解（MPB）之间的平衡来维持的，固定快速抑制MPS，导致肌肉萎缩。类似地，炎症直接影响调节MPS的途径，ICU患者表现出MPS减少和肌肉损失，VL IL-6增加100倍。因此，全身性炎症除了术后卧床不动外，还可能对全身肌肉产生显著的损伤作用。除了肌肉，全身性炎症通常导致免疫抑制。对这种免疫轻瘫的了解很少，但是出现了异常的中性粒细胞功能受损，其频率与感染和脓毒症的易感性增加有关。因此，没有有效、可行的干预措施来限制手术或创伤后的肌肉萎缩，全身炎症对肌肉失调和免疫抑制的负担尚不清楚。该项目将使用开发的新型稳定同位素技术，以便在术后恢复期间同时测量MPS和中性粒细胞周转率。在整个博士学位期间，申请人将有机会使用世界一流的设施，并接受肌肉骨骼研究领域领先专家的培训。在UoN的两所学校，学生将接受先进的代谢和分子生物学技术的培训，并学习该领域最前沿的尖端质谱技术。需要血液和肌肉活检收集学生将熟悉临床技能，并进一步花宝贵的时间在伯明翰BRC发展技能和知识，炎症研究和免疫抑制。

Immobilisation and inflammation are independently associated with significant muscle atrophy and when simultaneously present, result in catastrophic muscle mass loss that is associated with increased mortality. Muscle mass is maintained by the balance between muscle protein synthesis (MPS) and breakdown (MPB), with immobilisation rapidly supressing MPS resulting in muscle atrophy. Similarly, inflammation directly influences pathways modulating MPS, with ICU patients demonstrating reductions in MPS and muscle loss 100-fold increase in VL Il-6. Systemic inflammation is therefore likely to have significant damaging effects on whole body muscle, in addition to bed rest immobilisation post-surgery. Besides muscle, systemic inflammation often results in immune suppression. This immunoparesis is poorly understood, however there is an appearance of abnormal neutrophils with impaired function whose frequency is associated with increased susceptibility to infection and sepsis. As such there are no effective, feasible interventions to limit muscle atrophy after surgery or trauma, with the burden of systemic inflammation on muscle dysregulation and immunosuppression unknown. This project will use novel stable isotope techniques developed to enable simultaneous measurement of MPS and neutrophil turnover during post-surgical recovery. Throughout the PhD the applicant will have access to world-class facilities and receive training from leading experts within the field of musculoskeletal research. Being based across two schools at the UoN the student will receive training on advanced metabolic and molecular biology techniques and learn cutting-edge mass-spectrometry techniques at the forefront of the field. Requiring blood and muscle biopsies to be collected the student will be familiarised with clinical skills and further spend valuable time at the Birmingham BRC developing skills and knowledge in inflammatory research and immunosuppression.