Author:
Kakutani Naoya,Takada Shingo,Nambu Hideo,Matsumoto Junichi,Furihata Takaaki,Yokota Takashi,Fukushima Arata,Kinugawa Shintaro
Abstract
Abstract
Background
Transforming growth factor beta (TGF-β)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-β-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis.
Methods
Male C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery.
Results
Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-β and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1–7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure.
Conclusions
ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.
Funder
Grants-in-Aid for Scientific Research
Grant-in-Aid for Challenging Exploratory Research
Japan Foundation for Applied Enzymology
Hokkaido Heart Association Grant for Research
MSD Life Science Foundation
Uehara Memorial Foundation
Cardiovascular Research Fund, Tokyo, Japan
Fukuda Memorial Foundation for Medical Research
Kimura Memorial Heart Foundation Research Grant for 2017
SENSHIN Medical Research Foundation
Nakatomi Foundation
Japan Heart Foundation
Sasakawa Scientific Research Grant from The Japan Science Society
Center of Innovation Program from the Japan Science and Technology Agency
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology,Orthopedics and Sports Medicine
Cited by
10 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献