Effects of Evoked Resistance Training and Testosterone after Spinal Cord Injury

描述 患有脊髓损伤（SCI）的个体终生都有肥胖和几种慢性代谢紊乱的风险，如葡萄糖耐受不良、胰岛素抵抗和继发于身体成分恶化的血脂异常。在损伤的几周内，全身无脂肪质量（FFM）显著降低，特别是下肢骨骼肌质量，随后脂肪质量（FM）增加。阻力训练（RT）是一种重要的运动类型，已被证明可以诱导积极的生理适应，如增加瘦体重和减少其他临床人群的代谢紊乱。 在试点工作中，我们提供的证据表明，诱发RT使用表面神经肌肉电刺激（NMES）的膝伸肌群导致骨骼肌横截面积（CSA）显着增加，减少%腿FM和减少内脏脂肪组织（VAT）CSA的趋势。身体成分的良好适应与血浆胰岛素曲线下面积和血浆甘油三酯的降低有关。我们将身体组成和代谢特征的适应归因于血浆胰岛素样生长因子（IGF-1）的相关增加。我们的结论是，12周的诱发RT针对唤起骨骼肌肥大可能会导致显着的身体成分和代谢适应的SCI患者。 目前还不清楚超过12周的更长时间的RT计划是否会为SCI退伍军人提供额外的好处。目前还不清楚通过提供睾酮（T）替代疗法（TRT）来增强下降的合成代谢稳态是否会逆转SCI退伍军人的身体组成和代谢特征变化。本提案的主要研究目标是调查16周诱发RT+TRT与TRT对运动完全性SCI患者的身体组成（肌肉CSA、VAT、%FM）和代谢特征（葡萄糖和脂质代谢）的影响。为了实现这一目标，将每周两次进行表面NMES伴随踝关节负重，以从坐姿锻炼膝关节伸肌骨骼肌群。延迟入组4周后，受试者（n =24）将被随机分配到RT+TRT（n =12）或TRT（n =12）组。TRT将通过透皮T贴剂提供，在研究过程中，在双肩交替使用。我们还建议研究停训对身体成分和代谢特征的影响。研究计划包括三个由候选人和他的导师设计的具体目标。具体目标1将证明在16周训练+Tp和16周停止训练后，NMES RT和/或Tehran贴剂（Tp）对大腿和腿部骨骼肌群CSA、FFM百分比以及VAT CSA、肌内脂肪和FM百分比的影响。具体目标2将确定16周训练+Tp和停训后代谢环境（静息能量消耗、葡萄糖稳态、脂质谱、游离脂肪酸、血清总睾酮和游离睾酮以及IGF-1）和细胞因子（c-反应蛋白、肿瘤坏死因子α和IL-6作为炎症生物标志物）的变化。具体目标3将确定与仅Tp相比，16周的诱发RT和Tp是否会增加GLUT-4浓度、肌肉IGF-1和过氧化物酶体增殖物激活受体-γ共激活因子1（PGC-1）表达、改变纤维类型分布并增强线粒体酶活性（电子传递链）。

DESCRIPTION Individuals with spinal cord injury (SCI) are at a lifelong risk of increasing obesity and several chronic metabolic disorders such as glucose intolerance, insulin resistance and dyslipidemia secondary to deterioration in body composition. Within few weeks of injury, there are significant decrease in whole body fat-free mass (FFM), particularly lower extremity skeletal muscle mass and subsequent increase in fat mass (FM). Resistance training (RT) is an important type of exercise that has been shown to induce positive physiological adaptations such as increasing lean mass and reducing metabolic disorders in other clinical populations. In a pilot work, we provided evidence that evoked RT using surface neuromuscular electrical stimulation (NMES) for knee extensor muscle group resulted in significant increase skeletal muscle cross-sectional area (CSA), reduction in % leg FM and a trend towards decrease in visceral adipose tissue (VAT) CSA. The favorable adaptations in body composition were associated with decrease in plasma insulin area under the curve and plasma triglycerides. We attributed the adaptations in body composition and metabolic profile to an associated increase in plasma insulin-like growth factor (IGF-1). We concluded that twelve weeks of evoked RT targeted towards evoking skeletal muscle hypertrophy could result in significant body composition and metabolic adaptations in individuals with SCI. It is unclear if a longer RT program greater than 12 weeks would provide additional benefits to veterans with SCI. It is also unknown whether enhancing the decline anabolic homeostasis by providing testosterone (T) replacement therapy (TRT) would reverse body composition and metabolic profile changes in veterans with SCI. The major research goal of this proposal is to investigate the effects of 16 weeks of evoked RT+TRT vs. TRT on body composition (muscle CSA, VAT, %FM) and the metabolic profiles (glucose and lipid metabolism) in individuals with motor complete SCI. To address this goal, surface NMES accompanied with ankle weights will be conducted twice weekly to exercise the knee extensor skeletal muscle groups from sitting position. After 4 weeks of delayed entry approach, participants (n =24) will be randomly assigned into RT+TRT (n =12) or TRT (n =12) groups. The TRT will be provided via transdermal T patches that will be alternated on both shoulders over the course of the study. We also propose to study the effects of detraining on body composition and metabolic profiles. The research plan includes three specific aims that were devised by the candidate and his mentors. Specific aim 1 will demonstrate the effects of NMES RT and/or Testosterone patches (Tp) on the CSA of thighs and legs skeletal muscle groups, percentage FFM, and the CSA of VAT, intramuscular fat and percentage FM after 16 weeks of training+Tp and 16 weeks of detraining. Specific aim 2 will determine the changes in metabolic milieu (resting energy expenditure, glucose homeostasis, lipid profile, free fatty acids, serum total and free testosterone and IGF-1), and cytokines (c-reactive protein, tumor necrosis factor alpha and IL-6 as inflammatory biomarkers) after 16 weeks of training+Tp and detraining. Specific aim 3 will determine if 16 weeks of evoked RT and Tp will increase GLUT-4 concentration, muscle IGF-1 and peroxisome-proliferator-activated receptor-gamma co-activator 1 (PGC-1) expressions, altered fiber type distribution and enhance the mitochondrial enzymatic activities (electron transport chain) compared to Tp only.