Toledo Míriam, Busquets Sílvia, Penna Fabio, Zhou Xiaolan, Marmonti Enrica, Betancourt Angelica, Massa David, López-Soriano Francisco J, Han H Q, Argilés Josep M
Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
Int J Cancer. 2016 Apr 15;138(8):2021-9. doi: 10.1002/ijc.29930. Epub 2015 Dec 9.
Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.
福莫特罗是一种高效的β2 -肾上腺素能受体选择性激动剂，在许多动物物种中是一种肌肉生长促进剂。肌生成抑制素/激活素抑制可逆转骨骼肌丢失并延长荷瘤动物的生存期。本研究的目的是评估可溶性肌生成抑制素受体ActRIIB（sActRIIB）与β2 -激动剂福莫特罗联合使用在恶病质Lewis肺癌模型中的效果。福莫特罗和sActRIIB联合使用在逆转小鼠实验性癌症恶病质相关的肌肉消瘦方面极其有效。荷瘤动物的肌肉重量在治疗后完全恢复，这也反映在测量的握力上。这种联合用药增加了对照动物和荷瘤动物的食物摄入量。双重治疗还显著延长了生存期，而不影响原发肿瘤的重量和生长。此外，它显著减少了转移灶的数量。关于恶病质期间肌肉质量维持的机制，福莫特罗和sActRIIB的作用似乎是相加的，因为福莫特罗降低了蛋白质降解率（使用离体培养的单个肌肉，以酪氨酸释放量在体外测量），而sActRIIB仅影响蛋白质合成（使用氚标记的苯丙氨酸在体内测量）。福莫特罗还增加了蛋白质合成率，而sActRIIB的存在似乎有利于这一点。联合使用福莫特罗和sActRIIB似乎是治疗实验性癌症恶病质非常有前景的方法。对人类患者进行进一步研究是必要的，可能会为与癌症相关的肌肉消瘦带来一种高效的治疗选择。
