Characterization of the male Apc(Min/+) mouse as a hypogonadism model related to cancer cachexia

Cancer cachexia, the unintentional loss of lean body mass, is associated with decreased quality of life and poor patient survival. Hypogonadism, involving a reduction in circulating testosterone, is associated with the cachectic condition. At this time there is a very limited understanding of the role of hypogonadism in cancer cachexia progression. This gap in our knowledge is related to a lack of functional hypogonadal models associated with cancer cachexia. The Apc(Min/+) mouse is an established colorectal cancer model that develops an IL-6 dependent cachexia which is physiologically related to human disease due to the gradual progression of tumor development and cachexia. The purpose of this study was to assess the utility of the Apc(Min/+) mouse for the examination of hypogonadism during cancer cachexia and to investigate if IL-6 has a role in this process. We report that Apc(Min/+) mice that are weight stable have comparable testosterone levels and gonad size compared to wild type mice. Cachectic Apc(Min/+) mice exhibit a reduction in circulating testosterone and gonad size, which has a significant association with the degree of muscle mass and functional strength loss. Circulating testosterone levels were also significantly associated with the suppression of myofibrillar protein synthesis. Skeletal muscle and testes androgen receptor expression were decreased with severe cachexia. Although testes STAT3 phosphorylation increased with severe cachexia, systemic IL-6 over-expression for 2 weeks was not sufficient to reduce either testes weight or circulating testosterone. Inhibition of systemic IL-6 signaling by an IL-6 receptor antibody to Apc(Min/+) mice that had already initiated weight loss was sufficient to attenuate a reduction in testes size and circulating testosterone. In summary, the Apc(Min/+) mouse becomes hypogonadal with the progression of cachexia severity and elevated circulating IL-6 levels may have a role in the development of hypogonadism during cancer cachexia.