title: Muscle oxidative capacity during IL-6-dependent cancer cachexia.
abstract: 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.
authors.affiliation: Dept. of Exercise Science, University of South Carolina, Public Health Research Center, Rm. 405, 921 Assembly St., Columbia, SC 29208, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: White
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Baltgalvis
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Puppa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: John W
authors.initials: JW
authors.lastname: Baynes
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002374:Catalase / Q000235:genetics; D003110:Colonic Neoplasms / Q000150:complications*; D045304:Cytochromes c / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D017491:Genes, APC; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050796:STAT3 Transcription Factor / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000071247:Uncoupling Protein 3
chemical_list: D000447:Aldehydes; D004272:DNA, Mitochondrial; D015850:Interleukin-6; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000071247:Uncoupling Protein 3; D045304:Cytochromes c; D002374:Catalase; D013482:Superoxide Dismutase; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C027576:4-hydroxy-2-nonenal