title: PGC-1α promotes nitric oxide antioxidant defenses and inhibits FOXO signaling against cardiac cachexia in mice.
abstract: Chronic heart failure often results in catabolic muscle wasting, exercise intolerance, and death. Oxidative muscles, which have greater expression of the metabolic master gene peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target genes, are more resistant to catabolic wasting than are glycolytic muscles; however, the underlying mechanism is unknown. To determine the functional role of PGC-1α in oxidative phenotype-associated protection, skeletal muscle-specific PGC-1α transgenic mice were crossbred with cardiac-specific calsequestrin transgenic mice, a genetic model of chronic heart failure. PGC-1α overexpression in glycolytic muscles significantly attenuated catabolic muscle wasting induced by chronic heart failure. In addition to inactivation of forkhead transcription factor signaling through enhanced Akt/protein kinase B expression, in glycolytic muscles, PGC-1α overexpression led to enhanced expression of inducible nitric oxide synthase and endothelial nitric oxide synthase, production of nitric oxide, and expression of antioxidant enzyme including superoxide dismutases (SOD1, SOD2, and SOD3) and catalase, and reduced oxidative stress. These findings suggest that PGC-1α protects muscle from catabolic wasting in chronic heart failure through enhanced nitric oxide antioxidant defenses and inhibition of the forkhead transcription factor signaling pathways.
authors: Department of Medicine-Cardiovascular Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors: Tuoyu
authors: T
authors: Geng
authors: Ping
authors: P
authors: Li
authors: Xinhe
authors: X
authors: Yin
authors: Zhen
authors: Z
authors: Yan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D002100:Cachexia / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006019:Glycolysis; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D000975:Antioxidants; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen