Effects of Evoked Resistance Training and Testosterone after Spinal Cord Injury

描述 脊髓损伤(SCI)患者终生面临肥胖增加和几种慢性代谢疾病的风险，如葡萄糖耐量异常、胰岛素抵抗和血脂异常，继发于身体成分恶化。在伤后几周内，全身脱脂质量(FFM)显著下降，尤其是下肢骨骼肌质量显著下降，随后脂肪质量(FM)增加。抵抗力训练(RT)是一种重要的运动类型，已被证明可以在其他临床人群中诱导积极的生理适应，如增加瘦体重和减少代谢紊乱。在一项试点工作中，我们提供了证据表明，膝关节伸肌组使用表面神经肌肉电刺激(NMES)诱发的RT导致骨骼肌横截面积(CSA)显著增加，腿部FM百分比减少，内脏脂肪组织(VAT)CSA有下降的趋势。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减少有关。我们将身体成分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周的以诱发骨骼肌肥大为目标的诱导性RT可以导致脊髓损伤患者显著的身体成分和代谢适应。目前尚不清楚超过12周的较长时间的RT计划是否会为患有脊髓损伤的退伍军人提供额外的好处。通过提供睾酮(T)替代疗法(TRT)来增强合成代谢稳态的下降是否会逆转患有脊髓损伤的退伍军人的身体成分和代谢特征的变化也是未知的。本方案的主要研究目标是比较16周诱发RT+TRT与TRT对运动性完全性脊髓损伤患者的身体成分(肌肉CSA、VAT、%FM)和代谢谱(葡萄糖和脂代谢)的影响。为了实现这一目标，每周将进行两次表面NMES伴随着脚踝负重，以从坐位锻炼膝关节伸肌骨骼肌群。延迟入路4周后，受试者(n=24)随机分为RT+TRT组(n=12)或TRT组(n=12)。TRT将通过经皮T贴片提供，这种贴片将在研究过程中交替出现在两个肩膀上。我们还建议研究脱训对身体成分和代谢特征的影响。研究计划包括候选人和他的导师制定的三个具体目标。具体目标1将展示NMES RT和/或睾酮贴片(TP)对16周训练+TP和16周停训后大腿和腿部骨骼肌群的CSA、FFM百分比以及VAT、肌内脂肪和Fm百分比的CSA的影响。特定目标2将测定16周训练+TP和非训练后代谢环境(静息能量消耗、葡萄糖稳态、血脂、游离脂肪酸、血清总和游离睾酮及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。特异性目标3将确定16周的RT和TP是否会增加GLUT-4的浓度，肌肉IGF-1和PGC-1的表达，改变纤维类型分布，并增强线粒体酶活性(电子传输链)。

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.