Elevated PGC-1伪 Activity Sustains Mitochondrial Biogenesis and Muscle Function without Extending Survival in a Mouse Model of Inherited ALS

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• 作者：Sandrine Da  ; Cruz¹ ; ⁸ ; Philippe  ; A. Parone¹ ; ⁸ ; Vanda  ; S. Lopes⁴ ; Concepció ; n Lillo⁵ ; Melissa McAlonis-Downes¹ ; Sandra  ; K. Lee¹ ; Anne  ; P. Vetto¹ ; Susanna Petrosyan² ; Martin Marsala³ ; ⁶ ; Anne  ; N. Murphy² ; David  ; S. Williams⁴ ; Bruce  ; M. Spiegelman⁷ ; Don  ; W. Cleveland¹ ; ^{dcleveland@ucsd.edu}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：2 May, 2012
• 卷：15
• 期：5
• 页码：778-786
• 文件大小：1331 K

摘要

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Summary

The transcriptional coactivator PGC-1伪 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-1伪 levels in muscles of mice that develop fatal paralysis from an ALS-causing SOD1 mutant elevates PGC-1伪-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-1伪 activity in muscle represent an attractive therapy for maintaining muscle function during progression of ALS.