背景:脊髓和延髓性肌萎缩症(SBMA)是由三核苷酸胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复序列扩增引起的遗传性神经肌肉疾病,其编码雄激素受体(AR)基因中的聚谷氨酰胺(polyQ)束。最近的证据表明,除了运动神经元变性,骨骼肌缺陷也是SBMA发病机制的主要贡献者。虽然在SBMA中已经提出了体育锻炼的好处,潜在的机制仍然难以捉摸。
方法:我们研究了携带97个扩展CAG(AR97Q)的人AR的SBMA转基因小鼠模型中跑步运动的效果。我们将AR97Q小鼠分为运动和久坐对照组,运动组小鼠在疾病早期每周5天接受1-h强制运行轮(5m/min),持续4周。分析各组的运动功能(握力和旋转杆性能)和存活情况,并评估了骨骼肌和运动神经元的组织病理学和生物学特征。
结果:运动组的AR97Q小鼠表现出运动功能的改善(握力和旋转杆性能增加〜40%和〜50%,分别,P<0.05)和生存率(中位生存率23.6vs.16.7周,P<0.05)随着神经元和肌肉组织病理学的改善(运动神经元和肌纤维大小增加〜1.4倍和〜2.8倍,分别,P<0.001)与久坐组相比。与久坐的小鼠相比,运动小鼠骨骼肌和运动神经元中polyQ扩增的AR的核积累受到抑制(骨骼肌和运动神经元中1C2阳性细胞减少约50%和约30%,分别,P<0.05)。我们发现运动激活5'-一磷酸腺苷激活的蛋白激酶(AMPK)信号并抑制哺乳动物雷帕霉素途径的靶标,该途径调节SBMA小鼠骨骼肌中的蛋白质合成。AMPK的药理学激活抑制C2C12肌细胞中的蛋白质合成并减少polyQ扩增的AR蛋白。
结论:我们的研究结果表明,在SBMA中通过AMPK激活的运动诱导效应具有治疗潜力。
BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine-adenine-guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive.
METHODS: We investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5 m/min) 5 days a week for 4 weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated.
RESULTS: AR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P < 0.05) and survival (median survival 23.6 vs. 16.7 weeks, P < 0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P < 0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P < 0.05). We found that the exercise activated 5\'-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells.
CONCLUSIONS: Our findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.