Corrochano Silvia, Blanco Gonzalo, Acevedo-Arozena Abraham
Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, UK.
Department of Biology, University of York, York, UK.
J Exp Neurosci. 2018 Oct 30;12:1179069518809059. doi: 10.1177/1179069518809059. eCollection 2018.
Huntington's disease (HD) is a monogenic fatal neurodegenerative disorder. However, there is increasing evidence that HD is a pleiotropic systemic disorder. In particular, skeletal muscle metabolism is greatly affected in HD, which in turn can have a major impact on whole-body metabolism and energetic balance. Throughout an unbiased mutagenesis approach in HD mice, we have found that , a skeletal muscle-specific sodium channel gene, is a modifier of the disease. Mutations in enhance HD disease progression and weight loss by accelerating muscle waste and cachexia, increasing skeletal muscle activity and energy demands. At the molecular level, mutations activate AMP-activated protein kinase (AMPK), leading to a fibre switch towards more oxidative types. These adaptations seen in HD; double mutant muscles are similar to those observed in healthy individuals after endurance exercise training regimes. This prompted us to assess the effects of an endurance exercise regime in HD mice, independently showing that skeletal muscle adaptations leading to the activation of AMPK are detrimental for HD pathogenesis. Although it is undeniable that physical exercise can lead to many health benefits, our work shows that, at least under certain situations such as in HD, an endurance exercise routine could be a detrimental therapeutic option.
亨廷顿舞蹈症（HD）是一种单基因致死性神经退行性疾病。然而，越来越多的证据表明，HD是一种多效性全身疾病。特别是，HD患者的骨骼肌代谢受到极大影响，进而可能对全身代谢和能量平衡产生重大影响。通过对HD小鼠进行无偏向诱变方法，我们发现，一个骨骼肌特异性钠通道基因是该疾病的一个修饰基因。该基因的突变通过加速肌肉萎缩和恶病质、增加骨骼肌活性和能量需求，促进HD疾病进展和体重减轻。在分子水平上，该基因突变激活了AMP激活的蛋白激酶（AMPK），导致纤维类型向更具氧化性的类型转变。在HD双突变肌肉中观察到的这些适应性变化与健康个体在耐力运动训练后观察到的变化相似。这促使我们评估耐力运动方案对HD小鼠的影响，独立研究表明，导致AMPK激活的骨骼肌适应性变化对HD发病机制不利。尽管体育锻炼能带来诸多健康益处这一点不可否认，但我们的研究表明，至少在某些情况下，如在HD患者中，耐力运动常规可能是一种有害的治疗选择。
