Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria 3010, Australia.
Dis Model Mech. 2012 Jul;5(4):533-45. doi: 10.1242/dmm.008839. Epub 2012 Mar 22.
Cancer cachexia describes the progressive skeletal muscle wasting and weakness that is associated with many cancers. It impairs quality of life and accounts for >20% of all cancer-related deaths. The main outcome that affects quality of life and mortality is loss of skeletal muscle function and so preclinical models should exhibit similar functional impairments in order to maximize translational outcomes. Mice bearing colon-26 (C-26) tumors are commonly used in cancer cachexia studies but few studies have provided comprehensive assessments of physiological and metabolic impairment, especially those factors that impact quality of life. Our aim was to characterize functional impairments in mildly and severely affected cachectic mice, and determine the suitability of these mice as a preclinical model. Metabolic abnormalities are also evident in cachectic patients and we investigated whether C-26-tumor-bearing mice had similar metabolic aberrations. Twelve-week-old CD2F1 mice received a subcutaneous injection of PBS (control) or C-26 tumor cells. After 18-20 days, assessments were made of grip strength, rotarod performance, locomotor activity, whole body metabolism, and contractile properties of tibialis anterior (TA) muscles (in situ) and diaphragm muscle strips (in vitro). Injection of C-26 cells reduced body and muscle mass, and epididymal fat mass. C-26-tumor-bearing mice exhibited lower grip strength and rotarod performance. Locomotor activity was impaired following C-26 injection, with reductions in movement distance, duration and speed compared with controls. TA muscles from C-26-tumor-bearing mice had lower maximum force (-27%) and were more susceptible to fatigue. Maximum specific (normalized) force of diaphragm muscle strips was reduced (-10%) with C-26 injection, and force during fatiguing stimulation was also lower. C-26-tumor-bearing mice had reduced carbohydrate oxidation and increased fat oxidation compared with controls. The range and consistency of functional and metabolic impairments in C-26-tumor-bearing mice confirm their suitability as a preclinical model for cancer cachexia. We recommend the use of these comprehensive functional assessments to maximize the translation of findings to more accurately identify effective treatments for cancer cachexia.
癌症恶病质描述了与许多癌症相关的进行性骨骼肌消耗和无力。它会降低生活质量，并导致超过 20%的癌症相关死亡。影响生活质量和死亡率的主要结果是骨骼肌功能的丧失，因此临床前模型应该表现出类似的功能障碍，以最大限度地提高转化结果。携带结肠 26（C-26）肿瘤的小鼠通常用于癌症恶病质研究，但很少有研究对生理和代谢损伤进行全面评估，特别是那些影响生活质量的因素。我们的目的是描述轻度和重度恶病质小鼠的功能障碍，并确定这些小鼠作为临床前模型的适用性。代谢异常在恶病质患者中也很明显，我们研究了 C-26 荷瘤小鼠是否有类似的代谢异常。12 周龄的 CD2F1 小鼠接受皮下注射 PBS（对照）或 C-26 肿瘤细胞。18-20 天后，评估握力、转棒性能、运动活性、全身代谢以及胫骨前肌（原位）和膈肌肌条（体外）的收缩特性。C-26 细胞的注射减少了体重和肌肉质量以及附睾脂肪质量。C-26 荷瘤小鼠的握力和转棒性能较低。与对照组相比，C-26 注射后运动活性受损，运动距离、持续时间和速度降低。C-26 荷瘤小鼠的胫骨前肌最大力降低（-27%），更容易疲劳。膈肌肌条的最大比（归一化）力降低（-10%），疲劳刺激时的力也较低。与对照组相比，C-26 荷瘤小鼠的碳水化合物氧化减少，脂肪氧化增加。C-26 荷瘤小鼠的功能和代谢损伤范围和一致性证实了它们作为癌症恶病质临床前模型的适用性。我们建议使用这些全面的功能评估来最大限度地将研究结果转化，以更准确地确定癌症恶病质的有效治疗方法。
