Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus

IF 8.4 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetologia Pub Date : 2025-04-28 DOI:10.1007/s00125-025-06436-0

Christopher T. A. Lewis, Roger Moreno-Justicia, Lola Savoure, Enrique Calvo, Agata Bak, Jenni Laitila, Robert A. E. Seaborne, Steen Larsen, Hiroyuki Iwamoto, Marina Cefis, Jose A. Morais, Gilles Gouspillou, Jorge Alegre-Cebollada, Thomas J. Hawke, Jesús Vazquez, Miquel Adrover, Vincent Marcangeli, Rami Hammad, Jordan Granet, Pierrette Gaudreau, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, Atul S. Deshmukh, Julien Ochala

{"title":"Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus","authors":"Christopher T. A. Lewis, Roger Moreno-Justicia, Lola Savoure, Enrique Calvo, Agata Bak, Jenni Laitila, Robert A. E. Seaborne, Steen Larsen, Hiroyuki Iwamoto, Marina Cefis, Jose A. Morais, Gilles Gouspillou, Jorge Alegre-Cebollada, Thomas J. Hawke, Jesús Vazquez, Miquel Adrover, Vincent Marcangeli, Rami Hammad, Jordan Granet, Pierrette Gaudreau, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, Atul S. Deshmukh, Julien Ochala","doi":"10.1007/s00125-025-06436-0","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Disrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, we aimed to investigate whether it is altered in individuals with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We used vastus lateralis biopsy specimens (obtained from patients with type 2 diabetes and control participants with similar characteristics), and ran a combination of structural and functional assays consisting of loaded 2′- (or 3′)-<i>O-</i>(<i>N-</i>methylanthraniloyl)-ATP (Mant-ATP) chase experiments, x-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Our studies revealed a greater muscle myosin super-relaxation and decreased ATP demand in male participants with type 2 diabetes than in control participants. Subsequent proteomic analyses indicated that these (mal)adaptations probably originated from remodelled sarcomeric proteins and greater myosin glycation levels in patients than in control participants.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Overall, our findings indicate a complex molecular dysregulation of myosin super-relaxed state and energy consumption in male participants with type 2 diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through enhancement of ATP consumption.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\n","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"217 1","pages":""},"PeriodicalIF":8.4000,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetologia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00125-025-06436-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

Aims/hypothesis

Disrupted energy balance is critical for the onset and development of type 2 diabetes mellitus. Understanding of the exact underlying metabolic mechanisms remains incomplete, but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, we aimed to investigate whether it is altered in individuals with type 2 diabetes.

Methods

We used vastus lateralis biopsy specimens (obtained from patients with type 2 diabetes and control participants with similar characteristics), and ran a combination of structural and functional assays consisting of loaded 2′- (or 3′)-O-(N-methylanthraniloyl)-ATP (Mant-ATP) chase experiments, x-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres.

Results

Our studies revealed a greater muscle myosin super-relaxation and decreased ATP demand in male participants with type 2 diabetes than in control participants. Subsequent proteomic analyses indicated that these (mal)adaptations probably originated from remodelled sarcomeric proteins and greater myosin glycation levels in patients than in control participants.

Conclusions/interpretation

Overall, our findings indicate a complex molecular dysregulation of myosin super-relaxed state and energy consumption in male participants with type 2 diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through enhancement of ATP consumption.

Data availability

The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.

Graphical Abstract

查看原文本刊更多论文

2型糖尿病男性参与者骨骼肌肌球蛋白超松弛和能量学异常

目的/假设能量平衡紊乱对2型糖尿病的发生和发展至关重要。对确切的潜在代谢机制的了解仍不完整，但骨骼肌被认为在致病中起重要作用。由于其最丰富的蛋白质肌球蛋白的超放松状态调节细胞能量，我们的目的是研究它是否在2型糖尿病患者中发生改变。方法：我们使用股外侧肌活检标本（取自2型糖尿病患者和具有相似特征的对照组），并对分离肌纤维进行结构和功能分析，包括负载2 ' -（或3 '）- o -（n -甲基蒽酰）- atp （Mant-ATP）追踪实验、x射线衍射和LC-MS/MS蛋白质组学。结果我们的研究显示，与对照组相比，男性2型糖尿病患者肌球蛋白超松弛和ATP需求减少。随后的蛋白质组学分析表明，这些（不良）适应可能源于重塑的肌肉合成蛋白和患者比对照组更高的肌球蛋白糖基化水平。结论/解释总的来说，我们的研究结果表明，男性2型糖尿病患者肌球蛋白超放松状态和能量消耗存在复杂的分子失调。最终，肌球蛋白的药理靶向可以通过增强ATP的消耗来促进骨骼肌和全身代谢健康。数据可用性原始MS数据已通过PRIDE合作伙伴存储库（数据集标识符为PXD053022）存入ProteomeXchange Consortium。图形抽象

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

Diabetologia 医学-内分泌学与代谢

CiteScore

18.10

自引率

2.40%

发文量

193

审稿时长

1 months

期刊介绍： Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.