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

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.

Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue

“…Increased neuroinflammation, for example increased brain IL-1β expression, has been linked to both depressed mood [15] and fatigue [16]. Using a mouse model of CRF, we have previously shown that increased expression of pro-inflammatory cytokines within the CNS is associated with behavioral measures of fatigue, such as decreased voluntary wheel running (VWRA) activity, measures of weakness, such as reduced grip strength, and depressed mood, such as immobility during the forced swim test (FST) and anhedonia [17]. Treatment with minocycline, a drug that reduces brain synthesis of inflammatory cytokines, reduced depressive-like behaviors and improved grip strength in tumor-bearing mice [17].…”

Depression in cancer: The many biobehavioral pathways driving tumor progression

“…For instance, animal rat models of cancer-induced fatigue suggested that behavioral alterations occur in parallel with the increased expression of IL-1β mRNA in the cortex and the hippocampus 176 .…”

“…Fatigue significantly limits quality of life, reduces psychosocial functioning and is an independent predictor of decreased survival in individuals with terminal disease 175 . Recent advances in the neurobiology of fatigue revealed that it is more likely to be related to biological pathways promoting neuroinflammation than with primary alterations involving the muscles 176 .…”

Euflammation Attenuates Central and Peripheral Inflammation and Cognitive Consequences of an Immune Challenge after Tumor Development

“…Other peripheral tumors increase resting neuroinflammatory signals [39,40] and a rat model of breast cancer is characterized by exaggerated neuroinflammatory responses to a peripheral LPS injection relative to tumor-free controls [22]. Larger tumor masses may be necessary for these increases in resting and triggered neuroinflammatory signals, as a positive association between tumor mass and neuroinflammation has been observed [22].…”