Skeletal Muscle Wasting and Inflammatory Regulation by Ovarian Function and IL6 in Tumor Bearing Mice
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Cancer cachexia is a progressive wasting condition involving the loss of muscle and fat, as well as biochemical abnormalities due to chronic underlying disease such as cancer. IL6, a proinflammatory cytokine, has been shown to be a major driver of cancer cachexia in several mouse models, including the male ApcMin/+ (Min) mouse, and humans. Studies regarding cachexia and IL6 have largely been conducted in male mice; however, our lab has noted sex differences in cachexia development and IL6 response using the ApcMin/+ mouse. Inflammation related to IL6 signaling is associated with myofiber wasting in the male ApcMin/+ mouse, but it has been unexplored in the female. Though it has been seen that hypogonadism is a factor in cachexia in males, research has not been conducted to determine the effect of hypogonadism in the female. Given estrogen's known antiinflammatory effects, it is possible that ovarian endocrine function plays a role in the differential female IL6 response. The purpose of this study is to determine the effect of ovarian function and the role of IL6 in the muscle wasting seen during progression of cachexia. The hypothesis was that ovarian function loss (OVX) with IL6 overexpression would cause an increase in muscle inflammation, leading to increased myofiber wasting and decreased myofiber area. ApcMin/+ mice were divided among four groups: control (n=13), sham+IL6 overexpression (n=10), OVX+vector (n=10), OVX+IL6 (n=8). Tibialis anterior (TA) muscles were sectioned and mounted on slides. H&E staining was performed to determine myofiber crosssectional area (CSA). A greater proportion of small (<1500 m), and smaller proportion of large (>2000m) fibers were found in sham+IL6 mice vs. control mice (p<0.001), as well as in OVX+IL6 versus OVX+vector mice (p<0.001), indicating that IL6 overexpression induces a shift towards smaller fibers independent of ovarian function. Membrane receptor gp130, required for IL6 intracellular signaling, protein expression increased with IL6 overexpression and attenuated by OVX. OVX also decreased STAT3 phosphorylation, an intracellular mediator of IL6 signaling. Increased inflammation related to IL6 signaling is associated with muscle wasting in the female ApcMin/+ mouse and is attenuated by loss of ovarian function.Support or Funding InformationThe authors would like to acknowledge Justin Hardee, Dennis Fix, Song Gao, and Brandon VanderVeen for technical assistance. This research was funded by NIH grant NCI R01CA12124901.
