Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy
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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-01-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1112123/full |
| _version_ | 1797948273848221696 |
|---|---|
| author | Bo-ang Hu Yu-lin Li Hai-tao Han Bin Lu Xu Jia Lu Han Lu Han Wei-xuan Ma Ping Zhu Zhi-hao Wang Zhi-hao Wang Wei Zhang Ming Zhong Lei Zhang |
| author_facet | Bo-ang Hu Yu-lin Li Hai-tao Han Bin Lu Xu Jia Lu Han Lu Han Wei-xuan Ma Ping Zhu Zhi-hao Wang Zhi-hao Wang Wei Zhang Ming Zhong Lei Zhang |
| author_sort | Bo-ang Hu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T21:40:43Z |
| format | Article |
| id | doaj.art-ca6cf92e610e4cf6908eb978f784ae26 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T21:40:43Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-ca6cf92e610e4cf6908eb978f784ae262023-01-19T05:05:31ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-01-011410.3389/fphar.2023.11121231112123Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapyBo-ang Hu0Yu-lin Li1Hai-tao Han2Bin Lu3Xu Jia4Lu Han5Lu Han6Wei-xuan Ma7Ping Zhu8Zhi-hao Wang9Zhi-hao Wang10Wei Zhang11Ming Zhong12Lei Zhang13The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of General Practice, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Shandong key Laboratory of Cardiovascular Proteomics, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaBackground: 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.https://www.frontiersin.org/articles/10.3389/fphar.2023.1112123/fulldoxorubicinsoluble guanylate cyclaseskeletal muscle atrophyprotein synthesisprotein degradationvericiguat |
| spellingShingle | Bo-ang Hu Yu-lin Li Hai-tao Han Bin Lu Xu Jia Lu Han Lu Han Wei-xuan Ma Ping Zhu Zhi-hao Wang Zhi-hao Wang Wei Zhang Ming Zhong Lei Zhang Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy Frontiers in Pharmacology doxorubicin soluble guanylate cyclase skeletal muscle atrophy protein synthesis protein degradation vericiguat |
| title | Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy |
| title_full | Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy |
| title_fullStr | Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy |
| title_full_unstemmed | Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy |
| title_short | Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy |
| title_sort | stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy |
| topic | doxorubicin soluble guanylate cyclase skeletal muscle atrophy protein synthesis protein degradation vericiguat |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1112123/full |
| work_keys_str_mv | AT boanghu stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT yulinli stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT haitaohan stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT binlu stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT xujia stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT luhan stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT luhan stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT weixuanma stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT pingzhu stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT zhihaowang stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT zhihaowang stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT weizhang stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT mingzhong stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy AT leizhang stimulationofsolubleguanylatecyclasebyvericiguatreducesskeletalmuscleatrophyofmicefollowingchemotherapy |