Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli.
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.
Yu
Zengli
Z
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
Li
Ping
P
Zhang
Mei
M
Hannink
Mark
M
Stamler
Jonathan S
JS
Yan
Zhen
Z
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001284:Atrophy; D002100:Cachexia / Q000473:pathology / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D026422:S-Nitrosoglutathione / Q000494:pharmacology
D000975:Antioxidants; D004731:Endotoxins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione