title: Sex differences in the relationship of IL-6 signaling to cancer cachexia progression.
abstract: A devastating aspect of cancer cachexia is severe loss of muscle and fat mass. Though cachexia occurs in both sexes, it is not well-defined in the female. The Apc(Min/+) mouse is genetically predisposed to develop intestinal tumors; circulating IL-6 is a critical regulator of cancer cachexia in the male Apc(Min/+) mouse. The purpose of this study was to examine the relationship between IL-6 signaling and cachexia progression in the female Apc(Min/+) mouse. Male and female Apc(Min/+) mice were examined during the initiation and progression of cachexia. Another group of females had IL-6 overexpressed between 12 and 14 weeks or 15-18 weeks of age to determine whether IL-6 could induce cachexia. Cachectic female Apc(Min/+) mice lost body weight, muscle mass, and fat mass; increased muscle IL-6 mRNA expression was associated with these changes, but circulating IL-6 levels were not. Circulating IL-6 levels did not correlate with downstream signaling in muscle in the female. Muscle IL-6r mRNA expression and SOCS3 mRNA expression as well as muscle IL-6r protein and STAT3 phosphorylation increased with severe cachexia in both sexes. Muscle SOCS3 protein increased in cachectic females but decreased in cachectic males. IL-6 overexpression did not affect cachexia progression in female Apc(Min/+) mice. Our results indicate that female Apc(Min/+) mice undergo cachexia progression that is at least initially IL-6-independent. Future studies in the female will need to determine mechanisms underlying regulation of IL-6 response and cachexia induction.
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA.
authors.forename: Kimbell L
authors.initials: KL
authors.lastname: Hetzler
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Hardee
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Puppa
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA.
authors.forename: Aditi A
authors.initials: AA
authors.lastname: Narsale
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Davis
authors.affiliation: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, 921 Assembly St., Columbia, SC 29208 USA. Electronic address: carsonj@mailbox.sc.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000097:blood / Q000150:complications / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D002100:Cachexia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: Apc(Min/+); IL-6r; SOCS3; STAT3; Skeletal muscle