Cachexia Disrupts Diurnal Regulation of Activity, Feeding, and Muscle Mechanistic Target of Rapamycin Complex 1 in Mice.

INTRODUCTION: Cancer cachexia is characterized by severe skeletal muscle mass loss, which is driven by decreased muscle protein synthesis and increased protein degradation. Daily physical activity and feeding behaviors exhibit diurnal fluctuations in mice that can impact the systemic environment and skeletal muscle signaling. PURPOSE: We investigated the effect of cancer cachexia on the diurnal regulation of feeding, physical activity, and skeletal muscle mechanistic target of rapamycin complex 1 (mTORC1) signaling in tumor-bearing mice. We also examined the impact of increased physical activity on diurnal behaviors and skeletal muscle mTROC1 signaling in the cancer environment. METHODS: Physical activity and feeding behaviors were measured for four consecutive days before sacrifice in male C57BL/6 (B6; n = 24) and Apc (MIN; n = 22) mice at 7:00 AM and 7:00 PM under ad libitum condition. A subset of B6 (n = 16) and MIN (n = 19) mice were given wheel access for 2 wk before diurnal behavior measurements. Gastrocnemius muscle protein expression was examined. RESULTS: The MIN mice demonstrated altered diurnal fluctuations in feeding and activity compared with the B6. Interestingly, cachexia did not alter MIN total food intake, but dramatically reduced cage physical activity. As a measurement of mTORC1 activity, 4E-BP1 phosphorylation increased after the dark cycle in B6 and precachectic MIN mice, whereas rpS6 phosphorylation was only increased after the dark cycle in MIN mice. MIN 4E-BP1 phosphorylation at the end of the light cycle was significantly correlated with cachexia progression and reduced physical activity. Voluntary wheel running increased light cycle MIN 4E-BP1 phosphorylation and attenuated muscle mass loss. CONCLUSIONS: The cancer environment can alter diurnal feeding and physical activity behaviors in tumor-bearing mice, which are linked to the progression of cachexia and muscle wasting. Furthermore, suppressed physical activity during cachexia is associated with decreased skeletal muscle mTORC1 signaling

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin mice

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

OBESITY ACCELERATED TUMORIGENESIS AND DID NOT PROTECT AGAINST MURINE CANCER CACHEXIA

Thomas D. Cardaci, Brandon N. VanderVeen, Sierra J. McDonald, Brooke M. Bullard, Sarah S. Madero, Kandy T. Velazquez, FACSM, E. Angela Murphy. University of South Carolina School of Medicine, Columbia, SC. BACKGROUND: Cancer cachexia is the unintentional loss of lean mass and directly contributes to functional dependency, poor treatment outcomes, and decreased survival in cancer patients. Obesity has been suggested to protect against the severity of cachexia due to having ‘more to spare’; however, mechanistic support is lacking to promote obesity’s benefit. Further, obesity increases cancer risk contributing to the likelihood that cancer patients will be overweight or obese. Thus, the purpose of this study is to investigate the impact of obesity on cancer-induced skeletal muscle loss and function, survival, along with mitochondrial dysfunction and loss using the Lewis Lung Carcinoma (LLC) model of cancer cachexia. METHODS: Lean and obese C57/BL6 male mice (n=49) were implanted with LLC cells [1x106 cells] in the right flank or underwent sham surgery. Skeletal muscle was excised for transmission electron microscopy (TEM), histology, protein analysis, and cellular respiration 25 days following implantation or sham surgery. Cage activity and grip strength were assessed at day 0, 14, and 24. T-tests and mixed effects models were used to assess statistical differences. RESULTS: Obese LLC mice had increased tumor area (+Δ83%; p\u3c.001) and mass (+Δ176%; p\u3c.001), reduced survival (-Δ40%;p=.018), along with identical decreases in body weight (-Δ12%; p\u3c.001) and skeletal muscle mass loss (-Δ21%; p\u3c.001) compared to lean LLC mice. Preliminary TEM analysis unveils obese mice had greater evidence of mitochondrial dysfunction [auto(mito)phagic, altered cristae, contact area] (+Δ299%) regardless of LLC implantation, and identical decreases in mitochondrial content (-Δ47%) and area (-Δ53%) in obese and lean LLC mice. Cellular respiration (-Δ43%; p=.007), cage activity (-Δ66%; p\u3c.001), and relative grip strength (-Δ56%; p\u3c.001) were decreased in obese mice compared to lean mice but were not impacted by LLC implantation. CONCLUSIONS: Collectively, these data demonstrate obese mice had decreased survival and were not protected against skeletal muscle loss or mitochondrial perturbations associated with the LLC model of cancer cachexia. Moreover, our data highlight distinct obesity-dependent changes in muscle function and mitochondrial health which need to be explored further due their relevance in cancer-associated muscle wasting