Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A
Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A
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DOI：
10.1093/hmg/ddr427
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发表时间：
2011-12-15
影响因子：
3.5
通讯作者：
Durbeej, Madeleine
中科院分区：
文献类型：
--
作者：
Carmignac, Virginie;Svensson, Martina;Durbeej, Madeleine
由层粘连蛋白α2链缺陷引起的先天性肌营养不良症(又称MDC1A)是一种严重的致残疾病，以大量肌肉萎缩为特征。泛素-蛋白酶体系统在肌肉萎缩中起主要作用，我们最近证明，蛋白酶体活性增加是MDC1A的一个特征。自噬-溶酶体途径是参与肌肉细胞内蛋白质和细胞器降解的另一个主要系统。然而，自噬-溶酶体途径在包括MDC1A在内的肌营养不良症中是否存在失调仍有待确定。利用层粘连蛋白α2链缺陷的dy(3K)/dy(3K)小鼠模型和MDC1A患者肌肉，我们在这里展示了自噬相关基因在层粘连蛋白α2链缺陷的肌肉中表达上调。此外，我们发现自噬抑制显著改善了营养不良的dy(3K)/dy(3K)表型。特别是，我们发现全身注射3-甲基腺嘌呤(3-MA)可以减少肌肉纤维化、萎缩、细胞凋亡，增加肌肉再生和肌肉质量。重要的是，寿命和机车行为也得到了极大的改善。这些发现表明，增强的自噬活性是致病的，抑制自噬在治疗MDC1A方面具有很好的治疗潜力。
Congenital muscular dystrophy caused by laminin alpha 2 chain deficiency (also known as MDC1A) is a severe and incapacitating disease, characterized by massive muscle wasting. The ubiquitin-proteasome system plays a major role in muscle wasting and we recently demonstrated that increased proteasomal activity is a feature of MDC1A. The autophagy-lysosome pathway is the other major system involved in degradation of proteins and organelles within the muscle cell. However, it remains to be determined if the autophagy-lysosome pathway is dysregulated in muscular dystrophies, including MDC1A. Using the dy(3K)/dy(3K) mouse model of laminin alpha 2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is upregulated in laminin alpha 2 chain-deficient muscle. Moreover, we found that autophagy inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. In particular, we show that systemic injection of 3-methyladenine (3-MA) reduces muscle fibrosis, atrophy, apoptosis and increases muscle regeneration and muscle mass. Importantly, lifespan and locomotive behavior were also greatly improved. These findings indicate that enhanced autophagic activity is pathogenic and that autophagy inhibition holds a promising therapeutic potential in the treatment of MDC1A.