Integrative Muscle Biology Laboratory, Department of Exercise Science, Public Health Research Center, University of South Carolina, Columbia, SC 29208, USA.
Biol Open. 2013 Dec 15;2(12):1346-53. doi: 10.1242/bio.20136544.
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.
癌症恶病质，即非有意的去脂体重损失，与生活质量下降和患者预后不良有关。低睾酮血症，涉及循环睾酮的减少，与恶病质状态有关。目前，我们对低睾酮血症在癌症恶病质进展中的作用知之甚少。这种知识上的差距与缺乏与癌症恶病质相关的功能性低睾酮模型有关。Apc(Min/+) 小鼠是一种已建立的结直肠癌模型，它会发展出一种依赖于 IL-6 的恶病质，由于肿瘤发展和恶病质的逐渐进展，这种恶病质在生理上与人类疾病有关。本研究的目的是评估 Apc(Min/+) 小鼠在癌症恶病质期间检查低睾酮血症的效用，并研究 IL-6 是否在此过程中发挥作用。我们报告称，体重稳定的 Apc(Min/+) 小鼠与野生型小鼠相比，具有相当的睾酮水平和性腺大小。恶病质 Apc(Min/+) 小鼠表现出循环睾酮和性腺大小减少，这与肌肉质量和功能强度丧失的程度有显著关联。循环睾酮水平也与肌原纤维蛋白合成的抑制显著相关。随着恶病质的加重，骨骼肌和睾丸雄激素受体表达减少。尽管随着严重恶病质睾丸 STAT3 磷酸化增加，但全身 IL-6 过表达 2 周不足以降低睾丸重量或循环睾酮水平。用针对已开始体重减轻的 Apc(Min/+) 小鼠的 IL-6 受体抗体抑制全身 IL-6 信号足以减弱睾丸大小和循环睾酮的减少。总之，Apc(Min/+) 小鼠随着恶病质严重程度的进展而出现低睾酮血症，而升高的循环 IL-6 水平可能在癌症恶病质期间低睾酮血症的发展中起作用。
