Studies using dogs provide an ideal solution to the gap in animal models of natural disease and translational medicine. This is evidenced by approximately 400 inherited disorders being characterized in domesticated dogs, most of which are relevant to humans. There are several hundred isolated populations of dogs (breeds) and each has vastly reduced genetic variation compared to humans; this simplifies disease mapping and pharmacogenomics. Dogs age five to eight-fold faster than humans, share environments with their owners, are usually kept until old age, and receive a high level of health care. Farseeing investigators recognized this potential and, over the last decade, developed the necessary tools and infrastructure to utilize this powerful model of human disease, including the sequencing of the dog genome in 2005. Here we review the nascent convergence of genetic and translational canine models of spontaneous disease, focusing on cancer.

Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth.

Aims Fatigue is a common occurrence in cancer patients regardless of tumor type or anti-tumor therapies and is an especially problematic symptom in persons with incurable tumor disease. In rodents, tumor-induced fatigue is associated with a progressive loss of skeletal muscle mass and increased expression of biomarkers of muscle protein degradation. The purpose of the present study was to determine if muscle wasting and expression of biomarkers of muscle protein degradation occur in the hearts of tumor-bearing mice, and if these effects of tumor growth are associated with changes in systolic dysfunction. Main Methods The colon 26 adenocarcinoma cell line was implanted into female CD2F1 mice and skeletal muscle wasting, in vivo heart function, in vitro cardiomyocyte function, and biomarkers of muscle protein degradation were determined. Key Findings Expression of biomarkers of protein degradation were increased in both the gastrocnemius and heart muscle of tumor-bearing mice and caused systolic dysfunction in vivo. Cardiomyocyte function was significantly depressed during both cellular contraction and relaxation. Significance These results suggest that heart muscle is directly affected by tumor growth, with myocardial function more severely compromised at the cellular level than what is observed using echocardiography.

More than 500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. Dysregulation of the immune inflammatory response and the hypothalamic-pituitary-adrenal (HPA) axis are associated with depression in other populations. While significant research on the contribution of these systems to the development of PPD has been conducted, results have been inconclusive. This is partly because few studies have focused on whether disruption in the bidirectional and dynamic interaction between the inflammatory response and the HPA axis together influence PPD. In this study, we tested the hypothesis that disruption in the inflammatory-HPA axis bidirectional relationship would increase the risk of PPD. Plasma pro- and anti-inflammatory cytokines were measured in women during the 3rd trimester of pregnancy and on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for determination of cortisol area under the curve (AUC) and depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS). Of the 152 women who completed the EPDS, 18% were depressed according to EDPS criteria within the 6 months postpartum. Cortisol AUC was higher in symptomatic women on Day 14 (p=.017). To consider the combined effects of cytokines and cortisol on predicting symptoms of PPD, a multiple logistic regression model was developed that included predictors identified in bivariate analyses to have an effect on depressive symptoms. Results indicated that family history of depression, day 14 cortisol AUC, and the day 14 IL8/IL10 ratio were significant predictors of PPD symptoms. One unit increase each in the IL8/IL10 ratio and cortisol AUC resulted in 1.50 (P=0.06) and 2.16 (P=0.02) fold increases respectively in the development of PPD. Overall, this model correctly classified 84.2% of individuals in their respective groups. Findings suggest that variability in the complex interaction between the inflammatory response and the HPA axis influence the risk of PPD.

Cachexia is commonly seen in cancer and is characterized by severe muscle wasting, but little is known about the effect of cancer cachexia on expression of contractile protein isoforms such as myosin. Other causes of muscle atrophy shift expression of myosin isoforms toward increased fast (type II) isoform expression. We injected mice with murine C-26 adenocarcinoma cells, a tumor cell line that has been shown to cause muscle wasting. Mice were killed 21 days after tumor injection, and hindlimb muscles were removed. Myosin heavy chain (MHC) and myosin light chain (MLC) content was determined in muscle homogenates by SDS-PAGE. Body weight was significantly lower in tumor-bearing (T) mice. There was a significant decrease in muscle mass in all three muscles tested compared with control, with the largest decrease occurring in the soleus. Although no type IIb MHC was detected in the soleus samples from control mice, type IIb comprised 19% of the total MHC in T soleus. Type I MHC was significantly decreased in T vs. control soleus muscle. MHC isoform content was not significantly different from control in plantaris and gastrocnemius muscles. These data are the first to show a change in myosin isoform expression accompanying muscle atrophy during cancer cachexia.

Summary Chronic prenatal stress contributes to poor birth outcomes for women and infants. Importantly, poor birth outcomes are most common among minority and low income women. To investigate underlying mechanisms, we tested the hypothesis that chronic stress related to minority or low income status is associated with glucocorticoid resistance as indicated by disruption in the cytokine-glucocorticoid feedback circuit. Home visits were conducted during which 3rd trimester pregnant women completed stress and depression surveys and provided blood for pro- and anti-inflammatory cytokines. Saliva was collected 5 times the preceding day for diurnal cortisol levels. For statistical analyses, women were grouped 3 ways, by race, income, and the presence or absence of either of those risk factors; this last group was labeled high or low general risk. Immune regulation was evaluated by evidence of a functioning negative feedback relationship between cytokines and cortisol. Of 96 participants, 18 were minority, 22 of low income, and 29 either minority or low income (high general risk). Pearson partial correlation identified a significant negative relationship between cortisol area under the curve (AUC) and pro- to anti-inflammatory cytokine ratios in the low general risk women (i.e., Caucasian, higher income) including IFNγ/IL10 (r = −0.73, p < 0.0001), IL6/IL10 (r = 0.38, p = 0.01), IL1β/IL10 (r = −0.44, p = −0.004) and TNFα/IL10 (r = −0.41; p = 0.005); no such correlations existed in the high general risk women (i.e., minority, low income) for (IFNγ/IL10: r = −0.25, p = 0.43; IL6/IL10:r = 0.12, p = 0.70; IL1 β/IL10: r = 0.05, p = 0.87; TNFα/IL10: r = 0.10; p = 0.75), suggestive of glucocorticoid resistance. Cortisol levels throughout the day also were higher in minority and high general risk groups (p < 0.05). Without cytokine glucocorticoid feedback, a pregnant woman’s ability to regulate inflammation is limited, potentially contributing to adverse maternal and infant outcomes.

Fatigue is the most frequently reported symptom by cancer patients. Many of these patients perceive fatigue as the most distressing symptom associated with their illness because it imposes limitations on their physical activity level. Skeletal muscle wasting, which occurs as part of cancer cachexia, is one of the mechanisms that contribute to fatigue. Cancer-induced skeletal muscle wasting may occur despite normal food intake and is not prevented by nutritional supplementation. Evidence suggests that endurance exercise ameliorates cancer-related fatigue. There is no compelling evidence to support that exercise-induced reduction in fatigue is related to preservation of muscle mass. Resistance exercise attenuates muscle wasting associated with a variety of catabolic conditions. However, its effects on cancer-induced muscle wasting have not been adequately studied. This article describes the physiological mechanisms implicated in the induction of cancer-related muscle wasting, summarizes findings from endurance and resistance exercise studies in relation to fatigue and muscle wasting during cancer and selected clinical conditions, and proposes directions for future research.

Loss of food appetite is a common manifestation of acute infectious illness and is believed to contribute to the negative nitrogen balance and loss of body weight that is seen during infection. The frequency with which anorexia occurs with infection suggests that it may be part of the acute phase response. In the present experiments, food intake of fasted rats was suppressed following injection of interleukin-1, a polypeptide that mediates many host responses to infection. We conclude that infection-induced anorexia is, in part, due to the release of interleukin-1.