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

我们的长期目标是制定一项康复战略，以减轻有害的 脊髓损伤后去神经支配患者肌肉大小和小腿瘦体重的变化 脊髓损伤（SCI）。目前，运动功能低下后还没有可用的康复干预措施 神经元（LMN）去神经支配。超过46，000名退伍军人受到SCI的影响， 经历严重的骨骼肌萎缩和瘦体重减轻， 经历LMN去神经支配。骨骼肌的横截面积是6倍以下 LMN去神经支配与神经支配肌肉相比。失神经萎缩可能是 并伴有几种与SCI健康相关的后果。 12周，每周两次表面神经肌肉电刺激（NMES） 阻力训练（RT）可以引起骨骼肌尺寸增加35%以上， 异位脂肪组织积聚，SCI后胰岛素敏感性增加。而且 申请人的CDA-2初步研究结果表明，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，而TRT没有变化 只有团体。这伴随着基础代谢率（BMR）增加218 NMES-RT+TRT组中的kcal/天，TRT组中无变化。过程中 在这项研究的招募中，20%的SCI患者被排除在外，无法从 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）具有刺激 失神经肌肉和恢复肌肉大小的人与SCI。以前的模式 专注于每天激活失神经肌肉，而不施加渐进负荷 日常训练在SCI患者中不是临床可行的方法。此外，委员会认为， 之前的试验并没有关注通过促进神经肌肉的动态平衡来增强神经肌肉的动态平衡 瘦体重增加独立于LMN去神经支配。睾酮替代疗法 (TRT)已被证明可增加性腺功能减退男性的瘦体重和基础代谢率 关于SCI我们将确定TRT+LPWS是否会增加骨骼肌大小，腿部瘦体重， 并改善LMN去神经的SCI患者的整体代谢健康。我们假设 一年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增加整体线粒体健康。三个具体 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）， 大腿骨骼肌、肌内脂肪（IMF）和腿部瘦体重。目标2将决定 骨骼肌大小、腿部瘦体重和代谢变化之间的关联 通过测量BMR、血清脂质和碳水化合物谱确定的谱。目标3将 研究引起骨骼肌肥大的细胞机制 在TRT+LPWS之后。这项研究是新颖的，因为它提供了一个可行的康复 通过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失神经支配的人。如果证明成功，干预措施将很容易转化为 用于SCI患者的临床实践。

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.