SGLT2 inhibitor dapagliflozin mitigates skeletal muscle pathology by modulating key proteins involved in glucose and ion homeostasis in an animal model of heart failure

IF 4.2 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Elena Conte , Paola Imbrici , Giorgia Dinoi , Brigida Boccanegra , Martina Lanza , Elena Mele , Maria Antonietta Riemma , Konrad Urbanek , Donato Cappetta , Annamaria De Luca , Liberato Berrino , Antonella De Angelis , Antonella Liantonio
{"title":"SGLT2 inhibitor dapagliflozin mitigates skeletal muscle pathology by modulating key proteins involved in glucose and ion homeostasis in an animal model of heart failure","authors":"Elena Conte ,&nbsp;Paola Imbrici ,&nbsp;Giorgia Dinoi ,&nbsp;Brigida Boccanegra ,&nbsp;Martina Lanza ,&nbsp;Elena Mele ,&nbsp;Maria Antonietta Riemma ,&nbsp;Konrad Urbanek ,&nbsp;Donato Cappetta ,&nbsp;Annamaria De Luca ,&nbsp;Liberato Berrino ,&nbsp;Antonella De Angelis ,&nbsp;Antonella Liantonio","doi":"10.1016/j.ejphar.2025.177617","DOIUrl":null,"url":null,"abstract":"<div><div>Heart failure (HF) is a syndrome characterized by dyspnoea, fatigue and exercise intolerance. Among non-cardiac comorbidities which often accompany HF, skeletal muscle abnormalities impact patients’ daily activities and quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promise in improving clinical outcomes and enhancing physical performance in HF patients, although their mechanism of action remains unclear. In this context, altered muscle ions and glucose homeostasis may contribute to HF-related muscle changes and serve as indirect targets for SGLT2i effects. To explore this further, we used Dahl salt-sensitive rats fed with a high-salt diet for five weeks and then randomized to receive dapagliflozin (HS + DAP) or vehicle (HS) for the following six weeks. Control animals received a low-salt diet (LS). We investigated whether variations in indexes of glucose and ions homeostasis occur in extensor digitorum longus muscle of this rodent model of HF with preserved ejection fraction and are counteracted by dapagliflozin treatment. Gene and protein expression analysis revealed altered expression of proteins involved in glucose (SGLT2, GLUT4, GPD1) and Ca<sup>2+</sup> and Na <sup>+</sup> homeostasis (NCX3, Ryr1, NHE1/6, Na<sup>+</sup>/K<sup>+</sup>-ATPase, Nav1.4) in HS <em>vs</em> LS animals. Furthermore, HS rats showed an increased CaMKII expression in its active phosphorylated form and a change in plasma pH toward acidification. Dapagliflozin treatment counteracted the altered expression of most of the components under investigation, also promoting an amelioration of atrophy indexes and a recovery of plasma pH. Thus, skeletal muscle appears highly responsive to SGLT2i treatment, supporting the potential of these drugs in mitigating HF-related muscle pathology.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"997 ","pages":"Article 177617"},"PeriodicalIF":4.2000,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014299925003711","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Heart failure (HF) is a syndrome characterized by dyspnoea, fatigue and exercise intolerance. Among non-cardiac comorbidities which often accompany HF, skeletal muscle abnormalities impact patients’ daily activities and quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promise in improving clinical outcomes and enhancing physical performance in HF patients, although their mechanism of action remains unclear. In this context, altered muscle ions and glucose homeostasis may contribute to HF-related muscle changes and serve as indirect targets for SGLT2i effects. To explore this further, we used Dahl salt-sensitive rats fed with a high-salt diet for five weeks and then randomized to receive dapagliflozin (HS + DAP) or vehicle (HS) for the following six weeks. Control animals received a low-salt diet (LS). We investigated whether variations in indexes of glucose and ions homeostasis occur in extensor digitorum longus muscle of this rodent model of HF with preserved ejection fraction and are counteracted by dapagliflozin treatment. Gene and protein expression analysis revealed altered expression of proteins involved in glucose (SGLT2, GLUT4, GPD1) and Ca2+ and Na + homeostasis (NCX3, Ryr1, NHE1/6, Na+/K+-ATPase, Nav1.4) in HS vs LS animals. Furthermore, HS rats showed an increased CaMKII expression in its active phosphorylated form and a change in plasma pH toward acidification. Dapagliflozin treatment counteracted the altered expression of most of the components under investigation, also promoting an amelioration of atrophy indexes and a recovery of plasma pH. Thus, skeletal muscle appears highly responsive to SGLT2i treatment, supporting the potential of these drugs in mitigating HF-related muscle pathology.
在心力衰竭动物模型中,SGLT2抑制剂达格列净通过调节参与葡萄糖和离子稳态的关键蛋白来减轻骨骼肌病理
心力衰竭(HF)是一种以呼吸困难、疲劳和运动不耐受为特征的综合征。在常伴随HF的非心脏合并症中,骨骼肌异常影响患者的日常活动和生活质量。钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)在改善心衰患者的临床结果和增强身体机能方面显示出希望,尽管其作用机制尚不清楚。在这种情况下,肌肉离子和葡萄糖稳态的改变可能有助于hf相关的肌肉变化,并作为SGLT2i效应的间接靶点。为了进一步探讨这一点,我们使用高盐饮食喂养达尔盐敏感大鼠5周,然后在接下来的6周随机接受达格列净(HS + DAP)或载药(HS)。对照组给予低盐饮食(LS)。我们研究了保存射血分数的HF啮齿类动物模型的指长伸肌中葡萄糖和离子稳态指标的变化是否被达格列净治疗抵消。基因和蛋白表达分析显示,HS与LS动物中葡萄糖相关蛋白(SGLT2、GLUT4、GPD1)和Ca2+和Na+稳态相关蛋白(NCX3、Ryr1、NHE1/6、Na+/K+-ATPase、Nav1.4)的表达发生改变。此外,HS大鼠CaMKII活性磷酸化表达增加,血浆pH向着酸化方向变化。达格列净治疗抵消了研究中大多数成分的表达改变,也促进了萎缩指数的改善和血浆ph值的恢复。因此,骨骼肌对SGLT2i治疗表现出高度反应,支持这些药物在减轻hf相关肌肉病理方面的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.00
自引率
0.00%
发文量
572
审稿时长
34 days
期刊介绍: The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信