Paré Marie-France, Jasmin Bernard J
Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Front Neurol. 2017 Sep 27;8:516. doi: 10.3389/fneur.2017.00516. eCollection 2017.
Huntington's disease (HD) is an autosomal dominant neurodegenerative genetic disorder characterized by motor, cognitive, and psychiatric symptoms. It is well established that regular physical activity supports brain health, benefiting cognitive function, mental health as well as brain structure and plasticity. Exercise mimetics (EMs) are a group of drugs and small molecules that target signaling pathways in skeletal muscle known to be activated by endurance exercise. The EM 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) has been shown to induce cognitive benefits in healthy mice. Since AICAR does not readily cross the blood-brain barrier, its beneficial effect on the brain has been ascribed to its impact on skeletal muscle. Our objective, therefore, was to examine the effect of chronic AICAR treatment on the muscular and neurological pathology in a mouse model of HD. To this end, R6/2 mice were treated with AICAR for 8 weeks and underwent regular neurobehavioral testing. Under our conditions, AICAR increased expression of PGC-1α, a powerful phenotypic modifier of muscle, and induced the expected shift toward a more oxidative muscle phenotype in R6/2 mice. However, this treatment failed to induce benefits on HD progression. Indeed, neurobehavioral deficits, striatal, and muscle mutant huntingtin aggregate density, as well as muscle atrophy were not mitigated by the chronic administration of AICAR. Although the muscle adaptations seen in HD mice following AICAR treatment may still provide therapeutically relevant benefits to patients with limited mobility, our findings indicate that under our experimental conditions, AICAR had no effect on several hallmarks of HD.
亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性遗传疾病，其特征为运动、认知和精神症状。众所周知，规律的体育活动有助于大脑健康，对认知功能、心理健康以及大脑结构和可塑性均有益处。运动模拟物（EMs）是一类药物和小分子，它们靶向骨骼肌中已知可被耐力运动激活的信号通路。运动模拟物5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）已被证明可在健康小鼠中诱导认知益处。由于AICAR不易穿过血脑屏障，其对大脑的有益作用被归因于对骨骼肌的影响。因此，我们的目标是研究慢性AICAR治疗对HD小鼠模型中肌肉和神经病理学的影响。为此，R6/2小鼠接受AICAR治疗8周，并进行定期的神经行为测试。在我们的实验条件下，AICAR增加了肌肉强大的表型修饰因子PGC-1α的表达，并在R6/2小鼠中诱导了预期的向更具氧化型肌肉表型的转变。然而，这种治疗未能对HD进展产生益处。事实上，慢性给予AICAR并不能减轻神经行为缺陷、纹状体和肌肉中突变亨廷顿蛋白聚集密度以及肌肉萎缩。尽管AICAR治疗后HD小鼠出现的肌肉适应性变化可能仍会为行动不便的患者带来与治疗相关的益处，但我们的研究结果表明，在我们的实验条件下，AICAR对HD的几个标志性特征没有影响。
