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: Tuoyu Geng, Ping Li, Xinhe Yin, Zhen Yan
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 4 Pg. 1738-48 (Apr 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21435455 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Trans-Activators
• Transcription Factors
• Nitric Oxide
• Proto-Oncogene Proteins c-akt
• Oxygen

Topics

• Animals
• Antioxidants (chemistry, metabolism)
• Cachexia (metabolism)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Glycolysis
• Mice
• Muscle, Skeletal (metabolism)
• Myocardium (metabolism)
• Nitric Oxide (chemistry)
• Oxidative Stress
• Oxygen (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phenotype
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Trans-Activators (metabolism)
• Transcription Factors