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一种康复策略来减轻有害的脊柱后肌肉大小的变化和下腿瘦质量的变化绳索损伤（SCI）。目前，较低电动机后没有可用的康复干预措施神经元（LMN）神经支配。超过46,000名退伍军人受到SCI的影响，可能体验深刻的骨骼肌肉萎缩和瘦质量的损失和约20-25％体验LMN改造。骨骼肌横截面面积较小6倍与支配的肌肉相比，LMN的神经神经支配。神经萎缩可能是伴随着几个与SCI健康有关的后果。表面神经肌肉电刺激（NMES）的每周两次两次阻力训练（RT）可引起骨骼肌肉大小的35％以上，减少生态脂肪组织的积累，SCI后胰岛素敏感性提高。而且，申请人的CDA-2初步发现表明，NMES-RT和睾丸激素的16周替代疗法（TRT）将腿瘦质量增加1.5公斤，而TRT没有变化仅组。这是通过增加218的基本代谢率（BMR）来实现的 NMES-RT+TRT中的kcal/day在TRT组中没有任何变化。在该研究的招聘，有20％的SCI患者被排除在外，无法从中受益锻炼下肢肌肉，大概是由于LMN的神经支配。长脉冲宽度刺激（LPW； 120-150 ms）具有刺激的潜力剥夺了肌肉并恢复SCI患者的肌肉大小。以前的范式有专注于每天激活被取消的肌肉而不施加渐进式载荷类似于RT。对于患有SCI的人来说，日常培训不是临床上可行的方法。而且，以前的试验并未通过促进与LMN神经区无关的瘦质量增加。睾丸激素替代疗法（TRT）已显示出可增加瘦肉质量和基本代谢率与科幻。我们将确定TRT+LPW是否会增加骨骼肌肉大小，腿长质量并改善LMN改造的SCI患者的整体代谢健康。我们假设一年的TRT+LPWS方案将上调蛋白质合成途径，下降 - 调节蛋白质降解途径并增加总体线粒体健康。三个具体目标将解决这些假设。 AIM 1将评估TRT+LPW的影响 TRT+标准神经肌肉电刺激（NME；作为对照组）的大小大腿骨骼肌，肌内脂肪（IMF）和腿瘦质量。 AIM 2将确定骨骼肌大小，腿瘦质量的变化与代谢之间的关联通过测量BMR，血清脂质和碳水化合物剖面确定的轮廓。目标3意志研究负责唤起骨骼肌肥大的细胞机制遵循TRT+LPW。这项研究是新颖的，因为它提供了可行的康复通过结合两种方法来进行干预；这可能会改善科幻的生活质量具有LMN神经的人。如果被证明成功，干预措施将很容易翻译进入SCI患者的临床实践。