Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS.
Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS.
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DOI：
10.1016/j.cmet.2012.03.019
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发表时间：
2012-05-02
期刊：
影响因子：
29
通讯作者：
Cleveland DW
中科院分区：
文献类型：
--
作者：
Da Cruz S;Parone PA;Lopes VS;Lillo C;McAlonis-Downes M;Lee SK;Vetto AP;Petrosyan S;Marsala M;Murphy AN;Williams DS;Spiegelman BM;Cleveland DW
转录辅激活因子PGC-1α对肌肉产生多种作用，包括增加线粒体质量和活性。肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种进行性、致死性、成人发病的神经退行性疾病，其特征在于运动神经元的选择性丧失和骨骼肌变性。早期事件被认为是去神经诱导的肌肉萎缩，伴随着肌肉内线粒体活性和形态的改变。我们现在报告说，在ALS引起的SOD 1突变体导致致命性瘫痪的小鼠肌肉中，PGC-1α水平的升高会在整个疾病过程中升高PGC-1α依赖性途径。线粒体生物发生和活性在终末期疾病中得以维持，伴随着肌肉功能的保留、延迟的肌肉萎缩和即使在晚期疾病阶段也显著改善的肌肉耐力。然而，生存期并未延长。因此，肌肉不是突变SOD 1介导的毒性的主要靶点，但增加肌肉中PGC-1α活性的药物代表了在ALS进展期间维持肌肉功能的有吸引力的疗法。
The transcriptional coactivator PGC-1α induces multiple effects on muscle, including increased mitochondrial mass and activity. Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, adult-onset neurodegenerative disorder characterized by selective loss of motor neurons and skeletal muscle degeneration. An early event is thought to be denervation-induced muscle atrophy accompanied by alterations in mitochondrial activity and morphology within muscle. We now report that elevation of PGC-1α levels in muscles of mice that develop fatal paralysis from an ALS-causing SOD1 mutant elevates PGC-1α-dependent pathways throughout disease course. Mitochondrial biogenesis and activity are maintained through end-stage disease, accompanied by retention of muscle function, delayed muscle atrophy, and significantly improved muscle endurance even at late disease stages. However, survival was not extended. Therefore, muscle is not a primary target of mutant SOD1-mediated toxicity, but drugs increasing PGC-1α activity in muscle represent an attractive therapy for maintaining muscle function during progression of ALS.
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影响因子：
16.2
作者：
Israelson, Adrian;Arbel, Nir;Da Cruz, Sandrine;Ilieva, Hristelina;Yamanaka, Koji;Shoshan-Barmatz, Varda;Cleveland, Don W.
通讯作者：
Cleveland, Don W.
影响因子：
3.7
作者：
Vandevenne P;Lebrun M;El Mjiyad N;Ote I;Di Valentin E;Habraken Y;Dortu E;Piette J;Sadzot-Delvaux C
通讯作者：
Sadzot-Delvaux C
影响因子：
6.1
作者：
Holzbaur, Erika L. F.;Howland, David S.;Walsh, Frank S.
通讯作者：
Walsh, Frank S.
影响因子：
3.5
作者：
Pedrini S;Sau D;Guareschi S;Bogush M;Brown RH Jr;Naniche N;Kia A;Trotti D;Pasinelli P
通讯作者：
Pasinelli P
影响因子：
5.3
作者：
Kawamata, Hibiki;Manfredi, Giovanni
通讯作者：
Manfredi, Giovanni