Pötsch Mareike S, Ishida Junichi, Palus Sandra, Tschirner Anika, von Haehling Stephan, Doehner Wolfram, Anker Stefan D, Springer Jochen
Institute of Pharmacology and Toxicology, Faculty of Medicine, Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Charite Medical School, Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.
J Cachexia Sarcopenia Muscle. 2020 Apr;11(2):594-605. doi: 10.1002/jcsm.12537. Epub 2020 Feb 17.
Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia.
Young male Wistar Han rats were intraperitoneally inoculated with 10 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg , 3 mg kg MT-102, or placebo by gavage.
Three mg kg d MT-102 not only prevented progressive loss of fat mass (-6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. -37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. -60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg d MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg d MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16-0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively.
The present study shows that 3 mg kg MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.
恶病质是恶性肿瘤的常见表现，与骨骼肌和脂肪组织的消耗有关。在本研究中，我们在癌症恶病质大鼠模型中研究了一种新型的一流的合成代谢分解代谢转化剂对骨骼肌的影响。
将年轻雄性Wistar Han大鼠腹腔内接种10个吉田肝癌AH - 130细胞，每天通过灌胃给予0.3 mg/kg、3 mg/kg的MT - 102或安慰剂。
3 mg/kg/d的MT - 102不仅防止了脂肪量的逐渐减少（-6±2 g对-12±1 g；P<0.001）；瘦体重（+1±10 g对-37±2 g；P<0.001）和体重（+1±13 g对-60±2 g；P<0.001）得以维持。生活质量也得到改善，表现为食物摄入量增加（分别为12.9±3.1 g和4.3±0.5 g，3 mg/kg/d的MT - 102对安慰剂，P<0.001）以及在第11天自发活动增加（分别为52369±6521次计数/24小时和29509±1775次计数/24小时，3 mg·kg/d的MT - 102对安慰剂，P<0.01）。最重要的是，生存率提高（风险比=0.29；95%置信区间：0.16 - 0.51，P<0.001）。这些作用背后的分子机制分别通过测量蛋白酶体和半胱天冬酶-6活性或蛋白质印迹分析来评估，涉及整体蛋白质降解的减少和蛋白质合成的激活。
本研究表明，3 mg/kg的MT - 102减少分解代谢，同时在骨骼肌中诱导合成代谢，从而提高生存率。
