Influence of chronic moderate sleep restriction and exercise on inflammation and carcinogenesis in mice

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Abstract

The effects of chronic moderate sleep restriction and exercise training on carcinogenesis were examined in adenomatous polyposis coli multiple intestinal neoplasma (APC Min+/−) mice, a genetic strain which is predisposed to developing adenomatous polyposis. The mice were randomized to one of four 11 week treatments in a 2 × 2 design involving sleep restriction (by 4 h/day) vs. normal sleep and exercise training (1 h/day) vs. sedentary control. Wild-type control mice underwent identical experimental treatments. Compared with the wild-type mice, APC Min+/− mice had disrupted hematology and enhanced pro-inflammatory cytokine production from peritoneal exudate cells. Among the APC Min+/− mice, consistent interactions of sleep loss and exercise were found for measures of polyp formation, inflammation, and hematology. Sleep loss had little effect on these variables under sedentary conditions, but sleep loss had clear detrimental effects under exercise conditions. Exercise training resulted in improvements in these measures under normal sleep conditions, but exercise tended to elicit no effect or to exacerbate the effects of sleep restriction. Significant correlations of inflammation with polyp burden were observed. Among wild-type mice, similar, but less consistent interactions of sleep restriction and exercise were found. These data suggest that the benefits of exercise on carcinogenesis and immune function were impaired by chronic moderate sleep restriction, and that harmful effects of sleep restriction were generally realized only in the presence of exercise.

Highlight

► Sleep restriction attenuates or eliminates many of the benefits exercise has on reducing inflammation and carcinogenesis.

Introduction

In animals, prolonged sleep deprivation causes mortality (Rechtschaffen and Bergmann, 1995), and milder acute reductions in sleep can elicit altered immune function, increases in inflammatory substances, including cytokines, and multiple pathologies (Zielinski and Krueger, 2011, Besedovsky et al., 2012). These findings are consistent with human epidemiologic studies showing that short sleep (<6 h) is associated with mortality, including cancer-related mortality (Heslop et al., 2002, Hublin et al., 2007, Kripke et al., 1979). Short sleep is also associated with many morbidities, many of which are associated with chronic inflammation, such as colorectal adenoma (Thompson et al., 2011), type 2 diabetes (Cappuccio et al., 2010), hypertension (Gangwisch et al., 2006), cardiovascular disease (Meisinger et al., 2007), and obesity (Cappuccio et al., 2008).

However, limitations of experimental studies of sleep restriction in animals, as well as in humans, have been that they have been restricted to short term and/or profound manipulations of sleep duration. There is a need to examine the effects of chronic moderate sleep loss, which is likely more common in humans. Indeed, many scientists have posited causal associations of declines in sleep duration in recent decades with modern societal epidemics of obesity, diabetes, and certain cancers (Spiegel et al., 2009). However, available evidence from experimental studies of chronic sleep loss (>30 days) in humans has not indicated ill effects for many variables (Youngstedt et al., 2009, Zielinski et al., 2008).

In humans, regular physical activity is associated with a reduction in the incidence, progression, and reoccurrence of colorectal cancer (Wei et al., 2010). Moreover, exercise has consistently resulted in improvements in fatigue and sleep in cancer patients (Payne et al., 2008). Hence, moderate exercise training is a commonly prescribed adjunct treatment of cancer (De Nijs et al., 2008).

In mice, moderate exercise training has also been found to attenuate carcinogenesis (Zielinski et al., 2004, Mehl et al., 2005, Colbert et al., 2000), and to attenuate cancer-associated inflammation and pro-inflammatory cytokines. However, to our knowledge, the influence of exercise on carcinogenesis under conditions of sleep loss has never been investigated.

Conceivably, exercise could attenuate the effects of sleep loss on cancer and inflammation, analogous to its protective effects on other consequences of sleep loss, such as impairments in glucose tolerance (VanHelder et al., 1993). On the other hand, it is also plausible that exercise could exacerbate the effects of sleep loss, for example via enhanced fatigue or inflammation, which can also occur following exercise under some conditions (Walsh et al., 2011).

The adenomatous polyposis coli multiple intestinal neoplasma (APC Min+/−) mouse is a commonly used model for examining interventions that could influence cancer development. APC Min+/− mice are genetically identical to C57BL/6 mice but have a leucine codon truncated APC gene in codon 850 originating from an ethylnitrosourea mutation, which causes polyps to form in the small intestines and colon (Shoemaker et al., 1997). The APC gene mutation is similar to that found in people with familial adenomatous polyposis who develop sporadic colon cancer. Colorectal cancer development is associated with an APC mutation which activates the nuclear localization of the β-catenin and the Wnt pathway to activate growth factors such as pro-inflammatory cytokines to induce polyp formation (Terzic et al., 2010).

The aim of this study was to determine the effects of chronic moderate sleep restriction and exercise training on colorectal cancer development, hematological markers of immunity, and pro-inflammatory cytokines in APC Min+/−mice. A group of C57BL/6 wild-type mice were also assessed to compare changes in markers of inflammation and immunity in control mice not experiencing cancer development.

Section snippets

Animals and care

Seventy-four male APC Min+/− mice and 40 male C57BL/6J wild-type mice were obtained from breeding colonies purchased from Jackson Laboratory (Bar Harbor, ME). Mice were group housed 2–5 per cage by strain and maintained on a 12:12 h light:dark cycle (lights on 0700 h) with ad libitum access to food and water. The Institutional Animal Care and Usage Committee of the University of South Carolina approved all experiments.

Treatment randomization and acclimation

At 4 weeks of age, APC Min+/− mice were randomized to one of four 11-weeks

Adenomatous polyp quantity and burden

In theAPC Min+/− mice, a SLEEP-by-ACTIVITY interaction was observed [F(1, 70) = 19.367, p < 0.001] for intestinal polyps. Sleep restriction had little effect on intestinal polyp number under sedentary conditions. However, sleep restriction elicited a dramatic increase in intestinal polyps under exercise conditions (p < 0.001), which resulted in a main SLEEP effect [F(1, 70) = 23.202, p < 0.001] (Table 1). Moreover, whereas exercise elicited a modest increase in intestinal poly number under sleep

Discussion

Interactions between sleep restriction and exercise training were found for polyp development and peritoneal inflammatory cytokines. Sleep restriction had few effects under sedentary conditions, but numerous negative effects under exercise conditions. Whereas exercise elicited consistent reductions in inflammation and polyp formation under normal sleep conditions, these effects were attenuated or reversed under sleep restricted conditions. The effects of sleep restriction and exercise on

Acknowledgements

This research was supported by the National Institutes of Health (HL 71560 to SDY). We thank Matthew Davis, David Elliott, J. Larry Durstine, Marj Pena, and Frank Berger for their contributions to this research.

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