Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus
- PMID: 40295335
- PMCID: PMC12245971
- DOI: 10.1007/s00125-025-06436-0
Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus
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.
Keywords: Diabetes; Metabolism; Myosin; Skeletal muscle.
© 2025. The Author(s).
Conflict of interest statement
Data availability: The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022 [56]. The rest of the data that support the findings of this study are available from the corresponding author upon reasonable request. Funding: Open access funding provided by Copenhagen University. This work was generously funded by the Lundbeckfonden (R434-2023-311 to JO). The x-ray experiments were performed under approval of the SPring-8 Proposal Review Committee (2022 A1069). MS-based proteomics analyses were performed by the Proteomics Research Infrastructure at the University of Copenhagen, supported by the Novo Nordisk Foundation (grant agreement number NNF19SA0059305). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCIU, MICIU/AEI/10.13039/501100011033) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-zzzzS funded by MCIU). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. CTAL is an employee of Novo Nordisk A/S. This position began after the work on this manuscript was complete, and the position had no influence on the results or conclusions drawn. Contribution statement: CTAL, ASD and JO contributed to the study conception and design. Material preparation, data collection and analysis were performed by CTAL, RM-J, LS, EC, AB, JL, RAES, SL, HI, MC, JAM, GG, JA-C, TJH, JV, MA, VM, RH, JG, PG, MA-L, MB, RR, ASD and JO. The first draft of the manuscript was written by CTAL and JO, and all authors commented on all versions of the manuscript and approved the submitted version. JO is the guarantor of this work.
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