降低胆固醇加重SOD1G93A转基因小鼠病情进展：通过抑制AKT/mTOR通路加重肌肉损伤

The pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear and there is lack of effective treatment, therefore,delaying the development of disease is particularly important. The AKT/mTOR signaling pathway is important to the metabolism of muscle .Statins are widely used as lipid-lowering drugs and the AKT/mTOR signaling pathway plays an important role in statin-induced muscle toxicity. Previous literature reported that abnormal lipid metabolism is associated with ALS, but the exact mechanism is unknown. Our previous studies found abnormal cholesterol metabolism in the SOD1G93A transgenic mouse spinal cord, and decreased expression of HMG-R protein in muscle tissue with the progress of the disease. Therefore, we put forward a hypothesis that cholesterol reduction may inhibit the proteins synthesis of muscle cells carrying the mutant SOD1G93A gene by inhibiting the AKT/mTOR signaling pathway,then accelerate the disease progression. In this study, we use medicines to reduce cholesterol synthesis and increase cholesterol synthesis, to treat SOD1G93A transgenic mice and observe the phenotypic changes and the expression of related molecules of the AKT/mTOR signaling pathway in muscle tissue.Our aim is to prove that cholesterol reduction can aggravate muscle damage via inhibiting the AKT/mTOR pathway, thereby reveal that cholesterol reduction can accelerate ALS disease progression . The results can provide experimental and theoretical basis for improved lipid metabolism can delay progression of ALS.

肌萎缩侧索硬化发病机制不清，缺乏有效治疗方法，因此，延缓疾病进展尤为重要。AKT/mTOR 信号通路在肌肉代谢过程中有重要作用，临床降胆固醇药物-他汀类药物通过AKT/mTOR 信号通路致肌肉毒性。文献曾报道脂类代谢异常与ALS有关，具体机制不详。我们前期实验发现SOD1G93A转基因小鼠脊髓组织中胆固醇代谢障碍，肌肉组织中HMG-R表达随病情进展减少。因此提出假说，降低胆固醇通过AKT/mTOR通路，抑制ALS小鼠肌肉细胞蛋白合成，加速病情进展。本课题拟通过应用抑制胆固醇合成及增加胆固醇合成的药物干预SOD1G93A转基因小鼠，观察降低胆固醇对其表型变化及肌肉组织AKT/mTOR信号通路相关分子表达的影响，验证降低胆固醇通过抑制AKT/ mTOR通路加重SOD1G93A转基因小鼠的肌肉损伤，揭示降低胆固醇加重ALS疾病进展的机制，为改善脂类代谢能延缓ALS患者病情进展提供实验及理论依据。

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种致命的神经退行性疾病，其特征是选择性运动神经元丧失、肌肉萎缩和变性。其中散发性ALS（Sporadic ALS, SALS）约占90-95%，家族性ALS（Familial ALS, FALS）占5-10%。编码超氧化物歧化酶1（SOD1）的基因突变占家族性肌萎缩侧索硬化症的20%和散发性ALS病例的5%。 到目前为止，ALS的确切病因尚不清楚，没有任何治疗能显著改善患者的预后。他汀类药物作为3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，是目前临床上应用最广泛的药物治疗心脑血管疾病的药物，因为它能够降低低密度脂蛋白胆固醇还具有独立于固醇的作用（多效性），如抗炎、减轻氧化应激等。然而，他汀类药物因其罕见的他汀相关肌病及潜在的肌肉毒性较少用于临床。最新研究证实，他汀类药物减轻肌肉损伤、氧化应激，并改善肌肉功能。在这里我们研究了辛伐他汀类在G93ASOD1小鼠肌病中的作用，并且首次探讨了辛伐他汀干预G93ASOD1小鼠的肌肉病理变化。我们的结果表明辛伐他汀显著加重了G93ASOD1小鼠骨骼肌的自噬流缺陷、炎症反应、肌肉萎缩和纤维化。我们还发现炎症加重与肌肉萎缩和纤维化相关，并且通过自噬缺陷介导的炎症激活mTOR促进肌再生。然而，由于进行性失神经、肌萎缩而加重运动障碍，从而加重G93ASOD1小鼠表型。总之，我们的研究结果强调辛伐他汀加重骨骼肌萎缩和失神经支配，尽管促进了损伤肌肉再生，但基于他汀潜在的肌肉毒性和进行性去神经支配，仍需进一步的研究以明确他汀在ALS中的肌病作用的确切机制，为肌萎缩侧索硬化症的选择性应用他汀提供了新的见解。