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.

Extensive heterogeneity in myosin heavy chain and light chain (MLC) isoform expression in skeletal muscle has been well documented in several mammalian species. The initial objective of this study was to determine the extent of heterogeneity in myosin isoform expression among single fibers in limb muscles of dogs, a species for which relatively little has been reported. Fibers were isolated from muscles that have different functions with respect to limb extension and limb flexion and were analyzed on SDS gels, with respect to myosin isoform composition. The results of this part of the study indicate that there are at least four distinct fiber types in dog limb and diaphragm muscles, on the basis of MLC isoform expression: conventional fast (expressing fast-type isoforms of MLC1 (MLC1F) and MLC2 (MLC2F), plus MLC3), conventional slow (expressing slow-type MLC1 (MLC1S) and MLC2 (MLC2S)), hybrid (expressing MLC1S, MLC1F, MLC2S, MLC2F and MLC3) and a second slow fiber type, designated as S1F. S1F fibers express MLC1F, along with MLC1S and MLC2S and relatively low levels of MLC3. The fraction of slow fibers that are S1F fibers varies among dog limb muscles, being greater in limb extensors than flexors. Furthermore, the mean level of MLC1F in S1F fibers is greater in extensors than flexors (mean levels range from approximately 3% to 50% of total MLC1). The study was, therefore, extended to include six additional species, spanning a broad range in adult body size to more thoroughly characterize heterogeneity in MLC isoform expression among mammals. The results indicate that there are distinct patterns in MLC isoform expression among fast and slow fibers among different species. Specifically, large-size mammals have two distinct types of slow fibers, based upon MLC isoform composition (conventional and S1F fibers), whereas small mammals exhibit variations in MLC isoforms between different types of fast fibers, including a fast fiber type that expresses MLC1S (designated as F1S fibers). S1F fibers were absent in rodent muscles and F1S fibers were not found in large mammals. We conclude that extensive variation exists in MLC isoform expression in mammalian skeletal muscle fibers, yet there are distinct patterns among different species and among muscles within an individual species.

Aims Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines are associated with skeletal muscle wasting and depressive- and fatigue- like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF. Main Methods Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue-like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis. Key Findings Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1β and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice. Significance Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF.

MyHC isoform expression patterns differ markedly between and along global and orbital layers of dog rectus muscles, with greater complexity in the orbital layer. Heterogeneity in MyHC isoform expression in rectus muscles is much greater than in limb muscles and presumably is the basis for the broad spectrum of extraocular muscle (EOM) contractile properties in driving oculomotor functions.

Cardiac and skeletal muscle dysfunction is a recognized effect of cancerinduced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia.