Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli.

Abstract

Oxidative skeletal muscles are more resistant than glycolytic muscles to cachexia caused by chronic heart failure and other chronic diseases. The molecular mechanism for the protection associated with oxidative phenotype remains elusive. We hypothesized that differences in reactive oxygen species (ROS) and nitric oxide (NO) determine the fiber type susceptibility. Here, we show that intraperitoneal injection of endotoxin (lipopolysaccharide, LPS) in mice resulted in higher level of ROS and greater expression of muscle-specific E3 ubiqitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), in glycolytic white vastus lateralis muscle than in oxidative soleus muscle. By contrast, NO production, inducible NO synthase (iNos) and antioxidant gene expression were greatly enhanced in oxidative, but not in glycolytic muscles, suggesting that NO mediates protection against muscle wasting. NO donors enhanced iNos and antioxidant gene expression and blocked cytokine/endotoxin-induced MAFbx/atrogin-1 expression in cultured myoblasts and in skeletal muscle in vivo. Our studies reveal a novel protective mechanism in oxidative myofibers mediated by enhanced iNos and antioxidant gene expression and suggest a significant value of enhanced NO signaling as a new therapeutic strategy for cachexia.

• Authors: Zengli Yu, Ping Li, Mei Zhang, Mark Hannink, Jonathan S Stamler, Zhen Yan
• Journal: PloS one (PLoS One) Vol. 3 Issue 5 Pg. e2086 (May 07 2008) ISSN: 1932-6203 [Electronic] United States
• PMID: 18461174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Endotoxins
• Reactive Oxygen Species
• Nitric Oxide
• S-Nitrosoglutathione

Topics

• Animals
• Antioxidants (metabolism)
• Atrophy
• Cachexia (pathology, physiopathology)
• Endotoxins (toxicity)
• Gene Expression Regulation (drug effects)
• Glycolysis (drug effects)
• Mice
• Molecular Sequence Data
• Muscle Fibers, Skeletal (pathology, physiology)
• Muscle, Skeletal (pathology, physiopathology)
• Nitric Oxide (metabolism)
• Oxidative Stress (drug effects, physiology)
• Reactive Oxygen Species (metabolism)
• S-Nitrosoglutathione (pharmacology)