Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin, Madison, WI, USA.
McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Physiol Rep. 2020 Mar;8(5):e14391. doi: 10.14814/phy2.14391.
Cancer cachexia is the loss of lean muscle mass with or without loss of fat mass that is often highlighted by a progressive loss of skeletal muscle mass and function. The mechanisms behind the cachexia-related loss of skeletal muscle are poorly understood, including cachexia-related muscle functional impairments. Existing models have revealed some potential mechanisms, but appear limited to how the cancer develops and the type of tumors that form. We studied the C57BL6/J (B6) Apc Tg::Fabp1-Cre TG::PIK3ca* (CANCER) mouse. In this model, mice develop highly aggressive intestinal cancers. We tested whether CANCER mice develop cancer cachexia, if muscle function is altered and if sex differences are present. Both female and male mice, B6 (CONTROL) and CANCER mice, were analyzed to determine body weight, hindlimb muscle mass, protein concentration, specific force, and fatigability. Female CANCER mice had reduced body weight and hindlimb muscle mass compared with female CONTROL mice, but lacked changes in protein concentration and specific force. Male CANCER mice had reduced protein concentration and reduced specific force, but lacked altered body weight and muscle mass. There were no changes in fatigability in either group. Our study demonstrates that CANCER mice present an early stage of cachexia, have reduced specific force in male CANCER mice and develop a sex-dependent cachexia phenotype. However, CANCER mice lack certain aspects of the syndrome seen in the human scenario and, therefore, using the CANCER mice as a preclinical model does not seem sufficient in order to maximize the translation of preclinical findings to humans.
癌症恶病质是指肌肉减少，无论是否伴有脂肪减少，常以骨骼肌质量和功能进行性下降为特征。恶病质相关骨骼肌丢失的机制尚不清楚，包括恶病质相关肌肉功能障碍。现有的模型已经揭示了一些潜在的机制，但似乎仅限于癌症的发展和形成的肿瘤类型。我们研究了 C57BL6/J（B6）ApcTg::Fabp1-Cre TG::PIK3ca*（癌症）小鼠。在这种模型中，小鼠会发展出高度侵袭性的肠道癌。我们测试了癌症小鼠是否会发展恶病质，肌肉功能是否改变，以及是否存在性别差异。我们分析了雌性和雄性 B6（对照）和癌症小鼠，以确定体重、后肢肌肉质量、蛋白质浓度、比力和疲劳性。与雌性对照小鼠相比，雌性癌症小鼠的体重和后肢肌肉质量下降，但蛋白质浓度和比力没有变化。雄性癌症小鼠的蛋白质浓度降低，比力降低，但体重和肌肉质量没有改变。两组的疲劳性都没有变化。我们的研究表明，癌症小鼠呈现出恶病质的早期阶段，雄性癌症小鼠的比力降低，并表现出一种依赖于性别的恶病质表型。然而，癌症小鼠缺乏人类恶病质综合征的某些方面，因此，将癌症小鼠用作临床前模型似乎不足以最大限度地将临床前发现转化为人类。
