Cell Metabolism
Volume 15, Issue 5, 2 May 2012, Pages 778-786
Journal home page for Cell Metabolism

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

https://doi.org/10.1016/j.cmet.2012.03.019Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Muscle is not a primary target for mutant SOD1-mediated toxicity ► Enhanced PGC-1α activity sustains muscle function throughout ALS-like disease ► Improved muscle endurance does not prolong survival in a model of inherited ALS ► Increased PGC-1α activity in muscle is an attractive palliative therapy for ALS

Cited by (0)

8

These authors contributed equally to this work