Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy.
Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy.
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Vericiguat 刺激可溶性鸟苷酸环化酶可减少化疗后小鼠骨骼肌萎缩
DOI：
10.3389/fphar.2023.1112123
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
背景：化疗药物阿霉素（DOX）促进严重的骨骼肌萎缩，导致骨骼肌无力和疲劳。可溶性鸟苷酸环化酶（sGC）参与多种病理生理过程，但是否参与dox诱导的骨骼肌萎缩尚不清楚。本研究旨在用一种新的口服sGC刺激剂vericiguat刺激sGC，以测试其在这一过程中的作用。方法：将小鼠随机分为4组：对照组、vericiguat组、DOX组、DOX + vericiguat组。在小鼠被处死前评估运动能力。采用组织病理学和分子生物学方法评估骨骼肌萎缩。在小鼠和C2C12细胞中监测蛋白质的合成和降解。结果：本研究发现，DOX治疗后小鼠骨骼肌纤维运动能力和横截面积（CSA）明显下降。DOX降低小鼠和C2C12细胞的sGC活性，骨骼肌中骨骼肌纤维的CSA与sGC活性呈正相关。通过嘌呤霉素检测显示，DOX治疗还会损害蛋白质合成，并激活泛素-蛋白酶体途径。sGC刺激后肌纤维CSA升高，运动能力增强。刺激sGC还增加了蛋白质合成，降低了泛素-蛋白酶体途径。在潜在的机制方面，AKT/mTOR和fox01通路在DOX处理后受损，sGC刺激恢复了钝化的通路。结论：这些结果揭示了sGC刺激可以通过促进蛋白质合成和抑制蛋白质降解来改善小鼠对DOX治疗的骨骼肌萎缩和增加运动能力。刺激sGC可能是dox诱导的骨骼肌功能障碍的潜在治疗方法。
Background: The chemotherapeutic doxorubicin (DOX) promotes severe skeletal muscle atrophy, which induces skeletal muscle weakness and fatigue. Soluble guanylate cyclase (sGC) contributes to a variety of pathophysiological processes, but whether it is involved in DOX-induced skeletal muscle atrophy is unclear. The present study aimed to stimulate sGC by vericiguat, a new oral sGC stimulator, to test its role in this process. Methods: Mice were randomly divided into four groups: control group, vericiguat group, DOX group, and DOX + vericiguat group. Exercise capacity was evaluated before the mice were sacrificed. Skeletal muscle atrophy was assessed by histopathological and molecular biological methods. Protein synthesis and degradation were monitored in mice and C2C12 cells. Results: In this study, a significant decrease in exercise capacity and cross-sectional area (CSA) of skeletal muscle fibers was found in mice following DOX treatment. Furthermore, DOX decreased sGC activity in mice and C2C12 cells, and a positive correlation was found between sGC activity and CSA of skeletal muscle fibers in skeletal muscle. DOX treatment also impaired protein synthesis, shown by puromycin detection, and activated ubiquitin-proteasome pathway. Following sGC stimulation, the CSA of muscle fibers was elevated, and exercise capacity was enhanced. Stimulation of sGC also increased protein synthesis and decreased ubiquitin-proteasome pathway. In terms of the underlying mechanisms, AKT/mTOR and FoxO1 pathways were impaired following DOX treatment, and stimulation of sGC restored the blunted pathways. Conclusion: These results unravel sGC stimulation can improve skeletal muscle atrophy and increase the exercise capacity of mice in response to DOX treatment by enhancing protein synthesis and inhibiting protein degradation. Stimulation of sGC may be a potential treatment of DOX-induced skeletal muscle dysfunction.
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影响因子：
5.5
作者：
Haberecht-Müller S;Krüger E;Fielitz J
通讯作者：
Fielitz J
DOI：
10.1002/jcsm.12841
发表时间：
2022-03
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Das A;Gopinath SD;Arimbasseri GA
通讯作者：
Arimbasseri GA
DOI：
10.1073/pnas.74.8.3203
发表时间：
1977-01-01
影响因子：
11.1
作者：
ARNOLD, WP;MITTAL, CK;MURAD, F
通讯作者：
MURAD, F
影响因子：
3.3
作者：
Kavazis, Andreas N.;Smuder, Ashley J.;Powers, Scott K.
通讯作者：
Powers, Scott K.
影响因子：
7.2
作者：
Jiang, Bing;Yang, Yu-Jiao;Hu, Xu-Guang
通讯作者：
Hu, Xu-Guang