Musculoskeletal Plasticity after Spinal Cord Injury

 描述(由申请人提供)：脊髓损伤(SCI)患者经历代谢综合征、糖尿病、肥胖症、压疮和心血管疾病的几率远远高于普通人群。迫切需要一种康复方法来预防或逆转脊髓损伤的全身代谢后果。本研究的目的是确定能够增强氧化肌肉表型的肌肉活动剂量，并改善急性脊髓损伤患者代谢和骨转换健康的临床标记物。这项研究的长期目标是开发基于运动的干预措施，以预防糖尿病等次级健康状况，并最终保护与健康相关的生活质量(HRQOL)。具体目的1：比较接受高肌力站立(HS)、低肌力站立(LS)、被动站立(PS)和常规护理(无刺激和无站立，NS)16周的急性脊髓损伤患者骨骼肌基因调控的变化。我们假设代谢转录因子和调节糖酵解、脂肪酸氧化、三羧酸循环、氧化磷酸化和线粒体重塑的基因的mRNA表达将支持HS和LS比PS或NS更大地促进肌肉向氧化表型的转变。一项新的发现将是LS是骨骼肌中氧化途径的强大调节器。具体目标2：比较接受HS、LS、PS或NS治疗16周的脊髓损伤患者代谢健康和骨转换的系统标记物的变化。我们假设，与PS和NS相比，HS和LS在口服葡萄糖刺激期间将表现出更低的血糖/胰岛素水平和更大的胰高血糖素抑制。HS和LS还将显示较低的HOMA评分、血红蛋白A1c、成纤维细胞生长因子-21(FGF21)和胰升糖素样肽1(GLP-1)。LS将成为系统代谢标志物的有效调节剂。我们还假设HS将表现出比所有其他组(HS&GT；LS&GT；PS&GT；NS)更高的血清骨钙素水平，更低的1型胶原C-端肽(CTX)水平和更低的硬化素水平，这表明了对骨骼的抗分解代谢作用。作为次要目标，我们将衡量次级健康状况(SHCS)、HRQOL和成本效益。我们预计，与常规护理相比，HS、LS和PS组都将显示出改善SHCS和HRQOL的趋势。我们还希望看到新陈代谢的改善和对HRQOL感觉的改善之间的联系。这些观察结果将支持这一干预措施对未来的临床传输具有很强的可行性。

 DESCRIPTION (provided by applicant): Patients with spinal cord injury (SCI) experience metabolic syndrome, diabetes, obesity, pressure ulcers, and cardiovascular disease at far greater rates than the general population. A rehabilitation method to prevent or reverse the systemic metabolic consequences of SCI is a pressing need. The purpose of this study is to determine the dose of muscle activity that can enhance an oxidative muscle phenotype, and improve clinical markers of metabolic and bone turnover health in patients with acute SCI. The long-term goal of this research is to develop exercise-based interventions to prevent secondary health conditions such as diabetes and to ultimately protect health-related quality of life (HRQOL). Specific Aim 1: To compare changes in skeletal muscle gene regulation in individuals with acute SCI who receive high muscle force standing (HS), low muscle force standing (LS), passive standing (PS), or usual care - (no stimulation and no standing, NS) for 16 weeks. We hypothesize that mRNA expression for metabolic transcription factors and for genes regulating glycolysis, fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, and mitochondrial remodeling will support that HS and LS instigate a greater shift toward an oxidative muscle phenotype than PS or NS. A novel finding will be that LS is a powerful regulator of oxidative pathways in skeletal muscle. Specific Aim 2: To compare changes in systemic markers of metabolic health and bone turnover in individuals with SCI who receive HS, LS, PS, or NS for 16 weeks. We hypothesize that HS and LS will demonstrate lower glucose/insulin levels and greater glucagon suppression during oral glucose challenge compared to PS and NS. HS and LS will also demonstrate lower HOMA scores, hemoglobin A1c, fibroblast growth factor-21 (FGF21), and glucagon-like peptide 1 (GLP-1). LS will be an effective regulator of systemic markers of metabolism. We also hypothesize that HS will demonstrate higher serum levels of osteocalcin, lower levels of type 1 collagen C-telopeptide (CTX), and lower levels of sclerostin than all other groups (HS>LS>PS>NS), indicating an anti-catabolic effect on bone. As a secondary aim, we will measure secondary health conditions (SHCs), HRQOL, and cost effectiveness. We expect that the HS, LS, and PS groups will all show a trend for improved SHCs and HRQOL compared to usual care. We also expect to see an association between metabolic improvement and improved perception of HRQOL. These observations will support that this intervention has strong feasibility for future clinical translaion.