Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy
Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy
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DOI：
10.1007/s13311-015-0399-x
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
Caldero, Jordi
中科院分区：
文献类型：
--
作者：
Cervero, Claudia;Montull, Neus;Caldero, Jordi
脊髓性肌萎缩症（SMA）是一种以脊髓和脑干运动神经元（MN）缺失和骨骼肌麻痹为特征的遗传性神经肌肉疾病。目前，除了支持性治疗外，没有有效的治疗方法来改善SMA患者的生活质量。一些研究报告称，体育锻炼通过改善肌肉力量和运动功能，对SMA有潜在的益处。腺苷一磷酸活化蛋白激酶激动剂5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）已被报道为运动模拟剂，其能够调节肌肉代谢并在休息和运动期间增加耐力。已显示长期给予AICAR可改善mdx小鼠（杜氏肌营养不良模型）的营养不良肌肉表型和运动行为。在这里，我们研究了慢性AICAR治疗是否能够在重度SMA小鼠模型（SMN Delta 7小鼠）中对运动能力和神经肌肉组织病理学产生有益影响。我们报告说，AICAR改善骨骼肌萎缩和结构的变化，发现在SMN三角洲7动物的神经肌肉接头。然而，尽管AICAR防止MN上的神经元兴奋性突触的损失，但该化合物不能减轻MN损失或患病小鼠脊髓中发生的小胶质细胞和星形胶质细胞反应。此外，在用AICAR处理的SMN Delta 7动物中未观察到存活率或运动性能的改善。在我们的研究中发现，AICAR对SMA的有益作用是SMN无关的，因为在用该化合物治疗的患病动物的脊髓和骨骼肌中未观察到该蛋白质表达的变化。
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently, there is no effective treatment other than supportive care to ameliorate the quality of life of patients with SMA. Some studies have reported that physical exercise, by improving muscle strength and motor function, is potentially beneficial in SMA. The adenosine monophosphate-activated protein kinase agonist 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMN Delta 7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMN Delta 7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in survival or motor performance was seen in SMN Delta 7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, as no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound.