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Journal ArticleDOI

Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function.

01 Jan 2015-Brain Behavior and Immunity (Brain Behav Immun)-Vol. 43, pp 76-85

TL;DR: 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.
Abstract: 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.
Topics: Myosin (52%), Weakness (50%)

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1
Tumor Growth Increases Neuroinflammation, Fatigue and Depressive-like Behavior Prior 1
to Alterations in Muscle Function 2
3
Diana M. Norden
a
, Sabahattin Bicer
b
, Yvonne Clark
c
, Runfeng Jing
c
, Christopher J. Henry
a
, 4
Loren E. Wold
c,d
, Peter J. Reiser
b
, Jonathan P. Godbout
a,e
, and Donna O. McCarthy
5
6
a
Department of Neuroscience, The Ohio State University, 333 W. 10
th
Ave., Columbus, OH 7
43210. 8
b
Division of Biosciences, College of Dentistry, The Ohio State University, 305 W. 12
th
Ave., 9
Columbus, OH 10
c
College of Nursing, The Ohio State University, 1585 Neil Ave., Columbus, OH 11
d
Department of Physiology and Cell Biology, 370 W. 9
th
Ave., The Ohio State University, 12
Columbus, OH 13
e
Institute for Behavioral Medicine Research, The Ohio State University, 460 Medical Center Dr. 14
Columbus, OH 15
§
To whom correspondence should be addressed: Donna McCarthy, 235 Clark Hall, Marquette 16
University, P.O. Box 1881, Milwaukee WI, 53202-1881, Tel: 414-288-3820, Email: 17
donnalee.mccarthy@mu.edu 18
19
Key Words: fatigue, depression, neuroinflammation, cancer, minocycline, cytokines 20
21
22

2
Abstract 1
Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss 2
of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at 3
the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively 4
influences quality of life, limits functional independence, and is associated with decreased 5
survival in patients with incurable disease. Currently there are no effective treatments to reduce 6
CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between 7
two main components of fatigue: loss of muscle mass/function and altered mood/motivation. 8
Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced 9
body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased 10
depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-11
bearing mice within the first two weeks of tumor growth and preceded the loss of body and 12
muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not 13
associated with altered expression of myosin isoforms or impaired contractile properties of 14
muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased 15
expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced 16
tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved 17
grip strength without altering muscle mass. Taken together, these results indicate that 18
neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased 19
voluntary activity and precede major changes in muscle contractile properties with tumor 20
growth. 21
22

3
1. Introduction 1
Fatigue is the most common symptom reported by cancer patients before and during 2
treatment, and can continue for years after completion of treatment (Bower and Lamkin, 2013; 3
Husson et al., 2013; Minton et al., 2012). It often co-occurs with depression, (Bower et al., 2011; 4
Kim et al., 2012; Pertl et al., 2013) and reduces quality of life (Vissers et al., 2013). However, 5
the cause of cancer-related fatigue (CRF) is unknown (Berger et al., 2012) and there are no 6
effective treatments (Bower and Lamkin, 2013). 7
Mounting evidence indicates that CRF and depressed mood are associated with elevated 8
serum levels of pro-inflammatory mediators, including C-reactive protein (Pertl et al., 2013) and 9
cytokines such as tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β and IL-6 (Saligan and 10
Kim, 2012; Wood and Weymann, 2013). These cytokines are likely produced by the tumor and 11
host tissues in response to tumor growth or anti-tumor treatments (Wang et al., 2012). Pro-12
inflammatory cytokines increase expression of biomarkers of autophagy and the ubiquitin-13
proteasome pathway in skeletal muscle which reduce muscle mass (Fearon et al., 2012; Sandri, 14
2013; Toledo et al., 2011). The loss of muscle mass, or sarcopenia, can be seen even before 15
cancer treatment (Baracos et al., 2010; Cao et al., 2010) and likely explains patient complaints of 16
exhaustion associated with physical activity and muscle weakness (Hofman et al., 2007). 17
Systemic increases in pro-inflammatory mediators mount a complex response that is not 18
limited to the periphery. The central nervous system (CNS) interprets inflammatory responses 19
that originate in the periphery. Microglia, innate immune cells of the CNS, contribute to the 20
propagation of inflammatory cytokines and secondary messengers throughout the CNS (Wood 21
and Weymann, 2013). Increases in brain IL-1β are linked to both muscle atrophy (Braun et al., 22
2011) and depressed mood (Haroon et al., 2012). Recent evidence from rodent models indicates 23

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Cites background from "Tumor growth increases neuroinflamm..."

  • ...IL-1 and IL-6 in the brain, and treatment with minocycline, an anti-inflammatory agent, improved grip strength without reducing tumor growth or muscle mass [55]....

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  • ...[55] proposed a model to discriminate between these phenomena: some colon tumor-bearing mice demonstrated signs of fatigue (decreased voluntary wheel-running activity) and depressed mood (resignation and anhedonia), with no association with decreased normalized contractile properties of skeletal muscle of the limb....

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TL;DR: Progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.
Abstract: Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.

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  • ...The loss of muscle mass, or sarcopenia, can be seen even before 15 cancer treatment (Baracos et al., 2010; Cao et al., 2010) and likely explains patient complaints of 16 exhaustion associated with physical activity and muscle weakness (Hofman et al., 2007)....

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  • ..., 2010) and likely explains patient complaints of exhaustion associated with physical activity and muscle weakness (Hofman et al., 2007)....

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"Tumor growth increases neuroinflamm..." refers result in this paper

  • ...Consistent with other studies, tumor growth was associated with decreased body mass and muscle mass (Acharyya et al., 2004; Xu et al., 2011)....

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  • ...…hypothesis that 9 tumor induced cytokine-dependent changes in mood play a larger role in behaviors of CRF 10 compared to loss of skeletal muscle mass. 11 Consistent with other studies, tumor growth was associated with decreased body mass 12 and muscle mass (Acharyya et al., 2004; Xu et al., 2011)....

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