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

我们的长期目标是制定康复策略，以减轻 脊髓失神经患者的肌肉大小和小腿瘦质量的变化 脊髓损伤(SCI)。目前，还没有可用的低运动后康复干预措施。 神经元(LMN)失神经。超过46,000名退伍军人受到脊髓损伤的影响，可能 经历严重的骨骼肌萎缩和瘦体重减轻，约20%-25% 体验LMN去神经支配。骨骼肌横截面积比以下小6倍 与神经支配的肌肉相比，LMN的失神经。去神经萎缩可能是 伴随着几个与脊髓损伤健康相关的后果。 每周两次的12周表面神经肌肉电刺激(NMES) 阻力训练(RT)可导致骨骼肌大小增加35%以上，减少 异位脂肪组织积聚，脊髓损伤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，而TRT没有变化 仅限团体使用。随之而来的是基础代谢率(BMR)增加了218 NMES-RT+TRT组KCAL/d，TRT组无变化。在…的过程中 在这项研究中，20%的脊髓损伤患者被排除在外，无法从 锻炼他们的腿部肌肉，可能是因为失去了LMN的神经。 长脉宽刺激(LPWS；120-150ms)有可能刺激 去神经肌肉和恢复脊髓损伤患者的肌肉大小。以前的范例有 专注于不施加渐进性负荷的失神经肌肉的日常激活 类似于RT。日常训练对脊髓损伤患者来说不是一种临床可行的方法。此外， 以前的试验并没有集中于通过促进神经肌肉的动态平衡 瘦体重增加，不依赖于LMN去神经。睾酮替代疗法 (TRT)已被证明可以增加性腺功能低下男性的瘦体重和基础代谢率。 和SCI一起。我们将确定TRT+LPWS是否会增加骨骼肌大小、腿部瘦肉质量 改善去神经支配脊髓损伤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，提高线粒体整体健康水平。三个具体的 AIMS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)对大鼠 大腿骨骼肌、肌内脂肪(IMF)和腿部瘦肉质量。目标2将决定 骨骼肌大小、腿部瘦体重变化与代谢的关系 通过测量BMR、血脂和碳水化合物谱来确定其分布情况。目标3将 探讨诱发骨骼肌肥大的细胞机制 在TRT+LPWS之后。这项研究是新颖的，因为它提供了一种可行的康复 通过结合两种方法进行干预；这两种方法可能改善脊髓损伤患者的生活质量 有LMN失神经的人。如果被证明成功，这种干预将很容易转化为 应用于脊髓损伤患者的临床实践。

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.