Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS.

Abstract

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.

DOI: 10.1016/j.cmet.2012.03.019

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@article{Cruz2012ElevatedPA, title={Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS.}, author={Sandrine Da Cruz and Philippe A. Parone and Vanda S. Lopes and Concepci{\'o}n Lillo and Melissa McAlonis-Downes and Sandra K. Lee and Anne P. Vetto and Susanna Petrosyan and Martin Mar{\vs}ala and Anne N Murphy and David Steven Williams and Bruce M . Spiegelman and Don W Cleveland}, journal={Cell metabolism}, year={2012}, volume={15 5}, pages={778-86} }