Open Access 28-04-2025 | Type 2 Diabetes | Article

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

Published in: Diabetologia

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

Available only for authorised users

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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
Publication date: 28-04-2025
Publisher: Springer Berlin Heidelberg
Keyword: Type 2 Diabetes
Published in: Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-025-06436-0

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