4-hydroxy-2-nonenal and Cachexia

Many diseases are associated with catabolic conditions that induce skeletal muscle wasting. These various catabolic states may have similar and distinct mechanisms for inducing muscle protein loss. Mechanisms related to muscle wasting may also be related to muscle metabolism since glycolytic muscle fibers have greater wasting susceptibility with several diseases. The purpose of this study was to determine the relationship between muscle oxidative capacity and muscle mass loss in red and white hindlimb muscles during cancer cachexia development in the Apc(Min/+) mouse. Gastrocnemius and soleus muscles were excised from Apc(Min/+) mice at 20 wk of age. The gastrocnemius muscle was partitioned into red and white portions. Body mass (-20%), gastrocnemius muscle mass (-41%), soleus muscle mass (-34%), and epididymal fat pad (-100%) were significantly reduced in severely cachectic mice (n = 8) compared with mildly cachectic mice (n = 6). Circulating IL-6 was fivefold higher in severely cachectic mice. Cachexia significantly reduced the mitochondrial DNA-to-nuclear DNA ratio in both red and white portions of the gastrocnemius. Cytochrome c and cytochrome-c oxidase complex subunit IV (Cox IV) protein were reduced in all three muscles with severe cachexia. Changes in muscle oxidative capacity were not associated with altered myosin heavy chain expression. PGC-1α expression was suppressed by cachexia in the red and white gastrocnemius and soleus muscles. Cachexia reduced Mfn1 and Mfn2 mRNA expression and markers of oxidative stress, while Fis1 mRNA was increased by cachexia in all muscle types. Muscle oxidative capacity, mitochondria dynamics, and markers of oxidative stress are reduced in both oxidative and glycolytic muscle with severe wasting that is associated with increased circulating IL-6 levels.

Topics: Adipose Tissue; Aldehydes; Animals; Body Weight; Cachexia; Catalase; Colonic Neoplasms; Cytochromes c; DNA, Mitochondrial; Electron Transport Complex IV; Gene Expression; Genes, APC; GTP Phosphohydrolases; Hindlimb; Interleukin-6; Ion Channels; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Muscle; Mitochondrial Proteins; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Oxidative Phosphorylation; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sirtuin 1; STAT3 Transcription Factor; Succinate Dehydrogenase; Superoxide Dismutase; Trans-Activators; Transcription Factors; Uncoupling Protein 3

Oxidative stress is a primary trigger of cachectic muscle wasting, but the signaling pathway(s) that links it to the muscle wasting processes remains to be defined. Here, we report that activation of p38 mitogen-activated protein kinase (MAPK) (phosphorylation) and increased oxidative stress (trans-4-hydroxy-2-nonenal protein modification) in skeletal muscle occur as early as 8 h after lipopolysaccharide (1 mg/kg) and 24 h after dexamethasone (25 mg/kg) injection (intraperitoneal) in mice, concurrent with upregulation of autophagy-related genes, Atg6, Atg7, and Atg12. Treating cultured C2C12 myotubes with oxidant hydrogen peroxide (4 h) resulted in increased p38 phosphorylation and reduced FoxO3 phosphorylation along with induced Atg7 mRNA expression without activation of NF-kappaB or FoxO3a transcriptional activities. Furthermore, inhibition of p38alpha/beta by SB202190 blocked hydrogen peroxide-induced atrophy with diminished upregulation of Atg7 and atrogenes [muscle atrophy F-box protein (MAFbx/Atrogin-1), muscle ring finger protein 1 (MuRF-1), and Nedd4]. These findings provide direct evidence for p38alpha/beta MAPK in mediating oxidative stress-induced autophagy-related genes, suggesting that p38alpha/beta MAPK regulates both the ubiquitin-proteasome and the autophagy-lysosome systems in muscle wasting.

Topics: Aldehydes; Animals; Autophagy; Cachexia; Cell Line; Dexamethasone; Enzyme Activation; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; Glycolysis; Hydrogen Peroxide; Imidazoles; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 11; Mitogen-Activated Protein Kinase 14; Muscle Fibers, Skeletal; Muscular Atrophy; NF-kappa B; Oxidants; Oxidative Stress; Phosphorylation; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Pyridines; Signal Transduction; Transfection; Ubiquitination

UCP3 has been postulated to function in the defense against lipid-induced oxidative muscle damage (lipotoxicity). We explored this hypothesis during cachexia in rats (zymosan-induced sepsis), a condition characterized by increased oxidative stress and supply of fatty acids to the muscle. Muscle UCP3 protein content was increased 2, 6 and 11 days after zymosan injection. Plasma FFA levels were increased at day 2, but dropped below control levels on days 6 and 11. Muscular levels of the lipid peroxidation byproduct 4-hydroxy-2-nonenal (4-HNE) were increased at days 6 and 11 in zymosan-treated rats, supporting a role for UCP3 in modulating lipotoxicity during cachexia.

Topics: Aldehydes; Animals; Cachexia; Disease Models, Animal; Humans; Ion Channels; Lipid Peroxidation; Male; Mitochondrial Proteins; Muscle, Skeletal; Muscular Atrophy; Oxidation-Reduction; Oxidative Stress; Protein Biosynthesis; Rats; Rats, Wistar; Sepsis; Uncoupling Protein 3; Wasting Syndrome; Zymosan