Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy.
Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1alpha or its close homolog, PGC-1beta, influences muscle protein turnover. In myotubes, overexpression of either coactivator increased protein content by decreasing overall protein degradation without altering protein synthesis rates. Elevated PGC-1alpha or PGC-1beta also prevented the acceleration of proteolysis induced by starvation or FoxO transcription factors and prevented the induction of autophagy and atrophy-specific ubiquitin ligases by a constitutively active FoxO3. In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB. However, increasing muscle PGC-1alpha levels pharmacologically by treatment of mice with 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside failed to block loss of muscle mass or induction of ubiquitin ligases upon denervation atrophy, although it prevented loss of mitochondria. This capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.
Brault
Jeffrey J
JJ
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Jespersen
Jakob G
JG
Goldberg
Alfred L
AL
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001343:Autophagy; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D012265:Ribonucleotides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016328:NF-kappa B; D012263:Ribonucleosides; D012265:Ribonucleotides; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C031143:AICA ribonucleotide
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