title: Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice.
abstract: Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.
authors.affiliation: Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: Aditi A
authors.initials: AA
authors.lastname: Narsale
authors.affiliation: Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Puppa
authors.affiliation: Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Hardee
authors.affiliation: Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: Brandon N
authors.initials: BN
authors.lastname: VanderVeen
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: Reilly T
authors.initials: RT
authors.lastname: Enos
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: E Angela
authors.initials: EA
authors.lastname: Murphy
authors.affiliation: Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011759:Pyrrolidines / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013859:Thiocarbamates / Q000627:therapeutic use*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D011759:Pyrrolidines; D050796:STAT3 Transcription Factor; D013859:Thiocarbamates; C000613192:adenomatous polyposis coli protein, mouse; C020972:pyrrolidine dithiocarbamic acid
keywords: hepatomegaly; inflammation; metabolism; muscle atrophy; protein turnover