Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, Via di Val Cannuta, 00166, Rome, Italy.
Department of Clinical and Biological Sciences, IIM, University of Turin, Corso Raffaello, 10125, Turin, Italy.
J Cachexia Sarcopenia Muscle. 2017 Dec;8(6):954-973. doi: 10.1002/jcsm.12226. Epub 2017 Nov 11.
Cancer cachexia is characterized by muscle depletion and exercise intolerance caused by an imbalance between protein synthesis and degradation and by impaired myogenesis. Myofibre metabolic efficiency is crucial so as to assure optimal muscle function. Some drugs are able to reprogram cell metabolism and, in some cases, to enhance metabolic efficiency. Based on these premises, we chose to investigate the ability of the metabolic modulator trimetazidine (TMZ) to counteract skeletal muscle dysfunctions and wasting occurring in cancer cachexia.
For this purpose, we used mice bearing the C26 colon carcinoma as a model of cancer cachexia. Mice received 5 mg/kg TMZ (i.p.) once a day for 12 consecutive days. A forelimb grip strength test was performed and tibialis anterior, and gastrocnemius muscles were excised for analysis. Ex vivo measurement of skeletal muscle contractile properties was also performed.
Our data showed that TMZ induces some effects typically achieved through exercise, among which is grip strength increase, an enhanced fast-to slow myofibre phenotype shift, reduced glycaemia, PGC1α up-regulation, oxidative metabolism, and mitochondrial biogenesis. TMZ also partially restores the myofibre cross-sectional area in C26-bearing mice, while modulation of autophagy and apoptosis were excluded as mediators of TMZ effects.
In conclusion, our data show that TMZ acts like an 'exercise mimetic' and is able to enhance some mechanisms of adaptation to stress in cancer cachexia. This makes the modulation of the metabolism, and in particular TMZ, a suitable candidate for a therapeutic rehabilitative protocol design, particularly considering that TMZ has already been approved for clinical use.
癌症恶病质的特征是肌肉消耗和运动不耐受，这是由蛋白质合成和降解之间的失衡以及成肌障碍引起的。肌纤维代谢效率至关重要，以确保最佳的肌肉功能。一些药物能够重新编程细胞代谢，在某些情况下，还能提高代谢效率。基于这些前提，我们选择研究代谢调节剂曲美他嗪（TMZ）是否能够对抗癌症恶病质中发生的骨骼肌功能障碍和消耗。
为此，我们使用携带 C26 结肠癌细胞的小鼠作为癌症恶病质的模型。小鼠每天接受 5mg/kgTMZ（腹腔注射），连续 12 天。进行前肢握力测试，并切除比目鱼肌和腓肠肌进行分析。还进行了骨骼肌收缩特性的离体测量。
我们的数据表明，TMZ 诱导了一些通常通过运动达到的效果，其中包括握力增加、快肌向慢肌表型的转变增强、血糖降低、PGC1α 上调、氧化代谢和线粒体生物发生。TMZ 还部分恢复了 C26 荷瘤小鼠的肌纤维横截面积，而自噬和细胞凋亡的调节被排除为 TMZ 作用的介导物。
总之，我们的数据表明，TMZ 作为一种“运动模拟物”起作用，能够增强癌症恶病质中应激适应的一些机制。这使得代谢调节，特别是 TMZ，成为治疗性康复方案设计的合适候选物，特别是考虑到 TMZ 已经被批准用于临床使用。
