Targeting skeletal muscle to improve metabolic health in individuals with spinal cord injury

总结 拟议的研究项目检查了早期利用一种新的神经肌肉电 刺激（NMES）计划对骨骼肌代谢和整体代谢健康的影响 亚急性完全性脊髓损伤（SCI）。 背景：SCI患者比以前活得更长，并且活到代谢紊乱的年龄。 非常普遍。由于丧失活动能力和严重的骨骼肌萎缩、肥胖、葡萄糖耐受不良， 在SCI发病后不久就出现外周胰岛素抵抗。这些异常被认为有助于 增加糖尿病风险和加速SCI人群的衰老过程。的结果 这些趋势、并发症的总体负担、经济影响和生活质量下降正在增加。直到 SCI有有效的治疗方法，必须开发有效的干预措施，以减轻代谢 SCI患者出现的疾病。缺乏经验丰富的临床医生和研究人员， 有代谢健康和脊髓损伤方面的专业知识此外，缺乏适当的早期干预措施， 预防或降低损伤后代谢功能障碍的程度。 影响：SCI患者的人口增长和年龄增长需要新的和 采取跨学科的康复护理办法，以减轻经济负担， 生活质量 下一步：需要跨学科的康复研究人员领导必要的调查， 解决上述问题和挑战。作为这项培训和研究提案的候选人，我 我受过独特的训练，并有动力致力于我的职业生涯，以解决与 目前的趋势。我之前的研究和临床培训使我成为独立研究的理想人选。 在我的博士和博士后培训期间，我积极从事研究， 运动和营养干预，以改善SCI患者的肌肉骨骼和代谢健康。我 为这项研究带来了物理治疗和康复，人体生理学， 和骨骼肌生物学，正如我的出版记录所示。我的博士后经历培养了我的 通过将临床研究经验扩展到机制研究来指导真正的转化研究的能力 在骨骼肌和分子生物学中。我的工作的具体重点，我将建立在涉及 了解NMES对葡萄糖利用的细胞内信号通路活性的影响， 肌肉生长我负责SCI项目的所有方面-从受试者招募到临床研究， 在实验室进行分子和组织学分析。我的博士后实验揭示了新的发现， 其中一些在研究策略中有详细说明，为我的假设提供了强有力的支持。 提议这些实验的早期结果显示了快速有效地增加 糖尿病前期SCI患者胰岛素敏感性和肌肉表型改善 不使用药物。我对这些发现的热情是基于预防的潜力。 通过这项工作，我发现还有很多工作要做，更多的训练在间隔空间 学科（康复和代谢疾病）将提高我作为康复研究人员的效率。 我寻求NICHD赞助的K01奖，以支持对联合（阻力+有氧）NMES的研究 诱导优化个体代谢健康所必需的生理适应的训练方案 亚急性脊髓损伤此外，我将利用受保护的时间进行能量代谢，代谢组学， 以及临床试验设计和实施。这些活动最终将使我为一个富有成效的， 专注于将基础研究的发现转化为可行的临床研究 干预措施，以减少代谢性疾病的风险，在慢性阶段的SCI，而不使用 药我目前处于执行拟议调查的理想环境中， 组建了一个由知名科学家组成的指导团队， 干预方法。此外，我还可以使用最先进的研究实验室、核心设施， 设备以及从国家认可的康复医院招募病人的能力。 该项目的新颖之处在于严格审查了一个组合的影响（有氧+ 耐药性）NMES计划对骨骼肌代谢和新的靶向 代谢组学方法来了解肌肉适应对整体代谢健康的影响 SCI后立即（而不是研究去适应的慢性SCI）。如果正如假设的那样，SCI个体 在损伤后的6周内用组合NMES处方治疗， 质量和代谢以及整体代谢概况，未来的干预工作可以集中在1） 预防SCI急性期的负面肌肉适应，以及2）利用家庭基础 终身保持整体健康和生活质量的培训。

SUMMARY The proposed research project examines the impact of early utilization of a novel neuromuscular electrical stimulation (NMES) program on skeletal muscle metabolism and overall metabolic health in individuals with sub-acute, complete spinal cord injuries (SCI). Background: Individuals with SCI live longer than before and live to an age where metabolic disorders become highly prevalent. Due to loss of mobility and severe skeletal muscle atrophy, obesity, glucose intolerance, and peripheral insulin resistance develop soon after the onset of SCI. These abnormalities are thought to contribute to the increased diabetes disease risk and accelerated aging process in the SCI population. As a result of these trends, overall burden of complications, economic impact and reduced quality of life are increasing. Until there are effective treatments for SCI, it is imperative to develop effective interventions to mitigate metabolic disorders that develop in individuals with SCI. There is a lack of experienced clinicians and researchers who have expertise on metabolic health and SCI. Additionally, there is a lack of adequate early interventions to prevent or reduce the degree of metabolic dysfunction that follows injury. Implications: The growing population and increased age of individuals with SCI calls for novel and interdisciplinary rehabilitation approaches to care in order to reduce the economic burden and enhance the quality of life. Next Steps: Interdisciplinary rehabilitation researchers are needed to lead the investigations necessary to address the aforementioned problems and challenges. As a candidate for this training and research proposal, I am uniquely trained and motivated to commit my career to addressing the challenges associated with the current trends. My prior research and clinical training ideally position me for an independent research career. During my doctoral and post-doctoral training, I was actively engaged in research on the development of exercise and nutrition interventions to improve musculoskeletal and metabolic health in individuals with SCI. I bring to this research a diverse training background in physical therapy and rehabilitation, human physiology, and skeletal muscle biology as indicated by my publication record. My postdoctoral experience fostered my abilities to direct truly translational research by extending clinical research experiences to mechanistic studies in skeletal muscle and molecular biology. The specific focus of my work that I will build upon involved understanding the effects of NMES on activity of intracellular signaling pathways for glucose utilization and muscle growth. I conducted all aspects of SCI projects – from subject recruitment, to clinical studies, to molecular and histological assays in the laboratory. My postdoctoral experiments revealed novel findings, some of which are detailed in the Research Strategy, providing strong support for the hypotheses of my proposal. The early results of these experiments show exciting possibilities for a quick and effective increase in insulin sensitivity and improvements in muscle phenotype in individuals with SCI who have pre-diabetes without use of medication. My enthusiasm for these findings is based on the potential for prevention. Through this work, I have found there is much work to be done and that more training in the space between disciplines (rehabilitation and metabolic disease) will enhance my effectiveness as a rehabilitation researcher. I seek an NICHD-sponsored K01 award to support investigations of a combined (resistance + aerobic) NMES training protocol for inducing physiological adaptations necessary to optimize metabolic health in individuals with sub-acute SCI. In addition, I will use the protected time for training in energy metabolism, metabolomics, and clinical trial design and implementation. These activities will ultimately prepare me for a productive, independent career focused on translating findings from basic research into feasible, clinical interventions to reduce the risk of metabolic disease in the chronic stages of SCI without use of medication. I am currently in the ideal environment to execute the proposed investigations and have assembled a mentoring team of renowned scientists in in the disciplines necessary to integrate this intervention approach. Additionally, I have access to state-of-the-art research laboratories, core facilities and equipment as well as the ability to recruit patients from a nationally recognized rehabilitation hospital. The novelty of the proposed project lies in the rigorous examination of the effects a combined (aerobic + resistance) NMES program on skeletal muscle metabolism and in the application of novel targeted metabolomics approaches to understand the influence of muscle adaptations on overall metabolic health immediately after SCI (as opposed to studying deconditioned, chronic SCI). If, as hypothesized, SCI individuals treated with a combined NMES prescription over the 6 weeks following the injury maintain a healthy muscle mass and metabolism as well as overall metabolic profile, future intervention efforts can focus on 1) preventing negative muscle adaptations in the acute stages of SCI, and 2) utilizing home-based training for life-long maintenance of overall health and quality of life.