Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc Min/+ mice

Aditi A. Narsale, Melissa J. Puppa, Justin P. Hardee, Brandon N. VanderVeen, Reilly T. Enos, E. Angela Murphy, James Carson

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 Apc Min/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age Apc Min/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control Apc Min/+ 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.

Original languageEnglish (US)
Pages (from-to)59482-59502
Number of pages21
JournalOncotarget
Volume7
Issue number37
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Cachexia
Muscles
Liver
Tumor Burden
Interleukin-6
Body Weight
pyrrolidine dithiocarbamic acid
Neoplasms
Proteins
Muscle Proteins
Glycogen
Sulfhydryl Compounds
Energy Metabolism
Skeletal Muscle
Anti-Inflammatory Agents
Antioxidants
Inflammation
Lipids

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc Min/+ mice . / Narsale, Aditi A.; Puppa, Melissa J.; Hardee, Justin P.; VanderVeen, Brandon N.; Enos, Reilly T.; Murphy, E. Angela; Carson, James.

In: Oncotarget, Vol. 7, No. 37, 01.01.2016, p. 59482-59502.

Research output: Contribution to journalArticle

Narsale, Aditi A. ; Puppa, Melissa J. ; Hardee, Justin P. ; VanderVeen, Brandon N. ; Enos, Reilly T. ; Murphy, E. Angela ; Carson, James. / Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc Min/+ mice In: Oncotarget. 2016 ; Vol. 7, No. 37. pp. 59482-59502.
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