Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, Australia.
Am J Physiol Regul Integr Comp Physiol. 2013 May 15;304(10):R854-64. doi: 10.1152/ajpregu.00057.2013. Epub 2013 Mar 13.
Loss of skeletal muscle mass and function (cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20-29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls (P < 0.03). MoCR mice exhibited impaired rotarod performance and grip strength (P < 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity (P < 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue (P < 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases.
结直肠癌肝转移患者的骨骼肌质量和功能丧失（恶病质）非常严重，因为静息能量消耗大量增加，但由于缺乏合适的临床前模型，这种情况仍未得到充分研究。我们的目的是描述结直肠癌肝转移恶病质的一种新的临床前模型。我们检验了这样一个假设，即结直肠癌肝转移小鼠会出现恶病质，表现为肝无体质量、肌肉质量和生理功能障碍减少。12 周龄雄性 CBA 小鼠接受脾内注射 Ringer 溶液（假手术）或鼠结直肠癌细胞（MoCR）以诱导结直肠癌肝转移。在终点（20-29 天）时，MoCR 小鼠的肝脏完全浸润转移瘤，与 sham 对照组相比，MoCR 小鼠的肝无体质量、肌肉质量和附睾脂肪质量减少（P < 0.03）。MoCR 小鼠表现出旋转棒性能和握力受损（P < 0.03）。MoCR 小鼠比目鱼肌的组织化学分析显示肌肉纤维萎缩和氧化酶活性降低（P < 0.001）。MoCR 小鼠的脂肪组织重塑明显，脂肪细胞直径减小，非脂肪细胞组织浸润增加（P < 0.05）。这些发现表明 MoCR 小鼠模型表现出明显的恶病质，是结直肠癌肝转移恶病质的合适临床前模型。该模型应用于鉴定有效的恶病质治疗方法，以提高结直肠癌肝转移患者的生活质量并降低死亡率。
