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

摘要 这项拟议的研究项目考察了早期使用一种新型神经肌肉电的影响。 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。 背景：患有脊髓损伤的人比以前活得更长，并活到代谢紊乱成为 非常普遍。由于活动能力丧失和严重的骨骼肌萎缩、肥胖、糖耐量减低以及 外周胰岛素抵抗在脊髓损伤发病后不久就会发生。这些异常被认为是 对脊髓损伤人群中糖尿病疾病风险的增加和老龄化进程的加速。由于…… 这些趋势、并发症的总体负担、经济影响和生活质量下降都在增加。直到 脊髓损伤有有效的治疗方法，开发有效的干预措施来缓解代谢是当务之急。 在患有脊髓损伤的个体中发展起来的障碍。缺乏经验丰富的临床医生和研究人员 具有代谢健康和脊髓损伤方面的专业知识。此外，缺乏足够的早期干预措施来 预防或减轻损伤后代谢功能障碍的程度。 影响：日益增长的人口和年龄增长的脊髓损伤患者需要新颖和 跨学科的康复护理方法，以减轻经济负担并加强 生活质量。 下一步：需要跨学科的康复研究人员来领导必要的调查 解决上述问题和挑战。作为这项培训和研究计划的候选人，我 我受过独特的培训和激励，致力于解决与 当前的趋势。我之前的研究和临床培训为我的独立研究事业奠定了理想的地位。 在我的博士和博士后培训期间，我积极地从事关于 运动和营养干预以改善脊髓损伤患者的肌肉骨骼和代谢健康。我 为这项研究带来不同的训练背景，包括物理治疗和康复、人体生理学、 和骨骼肌生物学，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械性研究来指导真正的翻译研究的能力 在骨骼肌和分子生物学方面。我将以此为基础的工作的具体重点 了解NMES对葡萄糖利用和细胞内信号通路活性的影响 肌肉生长。我领导了SCI项目的方方面面--从受试者招募到临床研究，再到 实验室中的分子和组织分析。我的博士后实验发现了新的发现， 其中一些已在研究策略中详细说明，为我的假设提供了强有力的支持 求婚。这些实验的早期结果表明，快速有效地增加 糖尿病前期脊髓损伤患者的胰岛素敏感性和肌肉表型的改善 不需要药物治疗。我对这些发现的热情是基于预防的潜力。 通过这项工作，我发现有很多工作要做，在工作之余还有更多的培训 学科(康复和代谢性疾病)将提高我作为康复研究人员的效率。 我寻求由NICHD赞助的K01奖，以支持对联合(耐药+需氧)NMES的研究 用于诱导优化个体代谢健康所需的生理适应的训练方案 患有亚急性脊髓损伤。此外，我将利用受保护的时间进行能量代谢，代谢组学， 以及临床试验的设计和实施。这些活动最终将使我做好准备， 独立的职业生涯专注于将基础研究的结果转化为可行的临床研究 降低慢性脊髓损伤患者代谢性疾病风险的干预措施 药物治疗。我目前处于执行拟议调查的理想环境中，并且 组建了一个由著名科学家组成的指导团队，在必要的学科中整合这一 干预方法。此外，我还可以使用最先进的研究实验室、核心设施和 设备以及从国家认可的康复医院招募病人的能力。 拟议项目的新颖性在于对组合(有氧+ NMES程序对骨骼肌代谢的影响及其在新型靶向药物中的应用 了解肌肉适应对整体代谢健康影响的代谢组学方法 就在脊髓损伤之后(而不是研究解除条件的慢性脊髓损伤)。如果，正如假设的那样，SCI个人 在受伤后6周内接受NMES联合处方治疗，保持健康的肌肉 质量和新陈代谢以及整体新陈代谢情况，未来的干预努力可以集中在1) 预防脊髓损伤急性期的负性肌肉适应，以及2)利用家庭 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.