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Testosterone and Long Pulse Width Stimulation for Denervated Muscles after Spinal Cord Injury

脊髓损伤后失神经肌肉的睾酮和长脉冲宽度刺激

基本信息

批准号：
10612328
负责人：
Ashraf Gorgey
金额：
--
依托单位：
VA VETERANS ADMINISTRATION HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612328
关键词：
Action Potentials Address Adipose tissue Affect Area Atrophic Axon Basal metabolic rate Biochemical Biological Assay Biological Markers Biopsy Carbohydrates Cardiovascular Diseases Citrate (si)-Synthase Clinical Comb animal structure Complex Control Groups Data Degradation Pathway Denervation Down-Regulation Dual-Energy X-Ray Absorptiometry Electromyography Exercise Extensor FOXO1A gene FRAP1 gene Fasting Fatty acid glycerol esters Gene Proteins Goals Health Homeostasis Hour Individual Inflammatory Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Interleukin-6 Intervention Intramuscular Knee Leg Lipids Lower Extremity Magnetic Resonance Imaging Measurement Measures Metabolic Metabolic Diseases Mitochondria Motor Neurons Muscle Muscular Atrophy Needles OGTT Paralysed Participant Pathway interactions Persons Pharmacologic Substance Physical therapy Physiologic pulse Plasma Protein Biosynthesis Protocols documentation Quality of life Rehabilitation therapy Reporting Rewards Risk Serum Skeletal Muscle Spinal cord injury Subgroup Surface TNF gene Testosterone Therapeutic Intervention Thigh structure Thinness Time Training Translating Up-Regulation Veterans Width base cardiometabolism clinical practice density effectiveness evaluation experience high risk improved insulin sensitivity men metabolic profile muscle form muscle hypertrophy neuromuscular neuromuscular stimulation novel protein degradation protein expression recruit rehabilitation strategy response restoration skeletal muscle wasting strength training testosterone replacement therapy vastus lateralis

项目摘要

Our long-term goal is to develop a rehabilitation strategy to mitigate the deleterious changes in muscle size and lower leg lean mass in persons with denervation following spinal cord injury (SCI). Currently, there is no available rehabilitation intervention following lower motor neuron (LMN) denervation. More than 46,000 Veterans are affected with SCI and may experience profound skeletal muscle atrophy and loss of lean mass and about 20-25% experience LMN denervation. Skeletal muscle cross-sectional area is 6 times smaller following LMN denervation compared to the innervated muscles. Denervation atrophy may be accompanied by several SCI health-related consequences. Twelve weeks of twice weekly of surface neuromuscular electrical stimulation (NMES) resistance training (RT) can elicit more than a 35% increase in skeletal muscle size, decreased ectopic adipose tissue accumulation, increased insulin sensitivity after SCI. Moreover, the applicant’s CDA-2 preliminary findings showed that 16 weeks of NMES-RT and testosterone replacement therapy (TRT) increased leg lean mass by 1.5 kg with no changes in the TRT group only. This was accompanied by an increase in the basal metabolic rate (BMR) of 218 kcal/day in the NMES-RT+TRT with no changes in the TRT group. During the course of recruitment for the study, 20% of individuals with SCI were excluded and could not benefit from exercising their lower extremity muscles, presumably because of LMN denervation. Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in people with SCI. The previous paradigm has focused on daily activation of the denervated muscles without applying progressive loading similar to RT. Daily training is not a clinically feasible approach in persons with SCI. Moreover, previous trials did not focus on enhancing the neuromuscular homeostasis by promoting the increase in lean mass independent of LMN denervation. Testosterone replacement therapy (TRT) has been shown to increase lean mass and basal metabolic rate in hypogonadal men with SCI. We will determine if TRT+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in SCI persons with LMN denervation. We hypothesize that the one year TRT+LPWS protocol will upregulate protein synthesis pathways, down- regulate protein degradation pathways and increase overall mitochondrial health. Three specific aims will address these hypotheses. Aim 1 will assess the effects of TRT+LPWS compared to TRT+ standard neuromuscular electrical stimulation (NMES; as a control group) on the size of thigh skeletal muscle, intramuscular fat (IMF) and leg lean mass. Aim 2 will determine the association between the changes in skeletal muscle size, leg lean mass and the metabolic profile as determined by measuring BMR, serum lipids and carbohydrate profile. Aim 3 will investigate the cellular mechanisms responsible for evoking skeletal muscle hypertrophy following TRT+LPWS. This study is novel because it provides a feasible rehabilitation intervention by combining two approaches; which are likely to improve the quality of life in SCI persons with LMN denervation. If proven successful, the intervention will be easily translated into clinical practice for persons with SCI.

我们的长期目标是制定康复策略以减轻有害影响脊柱去神经术后患者肌肉大小和小腿瘦肉质量的变化脊髓损伤（SCI）。目前，尚无可用的下运动康复干预措施神经元（LMN）去神经支配。超过 46,000 名退伍军人受到 SCI 影响，可能经历严重的骨骼肌萎缩和瘦体重损失，约 20-25% 体验LMN去神经。骨骼肌横截面积缩小 6 倍如下 LMN 去神经支配与受神经支配的肌肉相比。失神经萎缩可能是伴随着一些 SCI 健康相关的后果。为期十二周，每周两次表面神经肌肉电刺激 (NMES) 阻力训练 (RT) 可使骨骼肌大小增加 35% 以上，异位脂肪组织堆积，SCI 后胰岛素敏感性增加。此外，申请人的 CDA-2 初步结果显示，16 周的 NMES-RT 和睾酮替代疗法 (TRT) 使腿部瘦体重增加 1.5 公斤，但 TRT 没有变化仅限团体。第 218 章 NMES-RT+TRT 组中的千卡/天，TRT 组中没有变化。期间该研究的招募中，20% 的 SCI 个体被排除在外，无法从研究中受益锻炼他们的下肢肌肉，大概是因为 LMN 去神经支配。长脉冲宽度刺激（LPWS；120-150 ms）有可能刺激去神经肌肉并恢复 SCI 患者的肌肉大小。之前的范式有专注于日常激活去神经支配的肌肉，而不施加渐进负荷与RT类似。对于 SCI 患者来说，日常训练在临床上并不是一种可行的方法。而且，之前的试验并未关注通过促进神经肌肉稳态来增强神经肌肉稳态瘦体重的增加与 LMN 去神经无关。睾酮替代疗法（TRT）已被证明可以增加性腺功能减退男性的瘦体重和基础代谢率与SCI。我们将确定 TRT+LPWS 是否会增加骨骼肌大小、腿部肌肉质量改善 LMN 去神经损伤 SCI 患者的整体代谢健康状况。我们假设一年的 TRT+LPWS 方案将上调蛋白质合成途径，下调调节蛋白质降解途径并提高线粒体的整体健康。三具体目标将解决这些假设。目标 1 将评估 TRT+LPWS 与 TRT+ 标准神经肌肉电刺激（NMES；作为对照组）对大腿骨骼肌、肌内脂肪 (IMF) 和腿部瘦体重。目标 2 将确定骨骼肌大小、腿部瘦肉质量和代谢变化之间的关系通过测量 BMR、血清脂质和碳水化合物概况来确定概况。目标3将研究引起骨骼肌肥大的细胞机制遵循TRT+LPWS。这项研究是新颖的，因为它提供了一种可行的康复方法结合两种方法进行干预；这可能会改善 SCI 患者的生活质量 LMN 去神经支配者。如果证明成功，干预措施将很容易转化进入 SCI 患者的临床实践。