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

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

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

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 GaudreauMylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, Atul S. Deshmukh, Julien Ochala^*

^*Corresponding author for this work

Centre for Human & Applied Physiological Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1836-1850
Number of pages	15
Journal	Diabetologia
Volume	68
Issue number	8
Early online date	28 Apr 2025
DOIs	https://doi.org/10.1007/s00125-025-06436-0
Publication status	E-pub ahead of print - 28 Apr 2025

Keywords

Diabetes
Metabolism
Myosin
Skeletal muscle

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lewis, C. T. A., Moreno-Justicia, R., Savoure, L., Calvo, E., Bak, A., Laitila, J., Seaborne, R. A. E., Larsen, S., Iwamoto, H., Cefis, M., Morais, J. A., Gouspillou, G., Alegre-Cebollada, J., Hawke, T. J., Vazquez, J., Adrover, M., Marcangeli, V., Hammad, R., Granet, J., ... Ochala, J. (2025). Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus. Diabetologia, 68(8), 1836-1850. Advance online publication. https://doi.org/10.1007/s00125-025-06436-0

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title = "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",

author = "Lewis, {Christopher T.A.} and Roger Moreno-Justicia and Lola Savoure and Enrique Calvo and Agata Bak and Jenni Laitila and Seaborne, {Robert A.E.} and Steen Larsen and Hiroyuki Iwamoto and Marina Cefis and Morais, {Jose A.} and Gilles Gouspillou and Jorge Alegre-Cebollada and Hawke, {Thomas J.} and Jes{\'u}s Vazquez and Miquel Adrover and Vincent Marcangeli and Rami Hammad and Jordan Granet and Pierrette Gaudreau and Myl{\`e}ne Aubertin-Leheudre and Marc B{\'e}langer and Richard Robitaille and Deshmukh, {Atul S.} and Julien Ochala",

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doi = "10.1007/s00125-025-06436-0",

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Lewis, CTA, Moreno-Justicia, R, Savoure, L, Calvo, E, Bak, A, Laitila, J, Seaborne, RAE, Larsen, S, Iwamoto, H, Cefis, M, Morais, JA, Gouspillou, G, Alegre-Cebollada, J, Hawke, TJ, Vazquez, J, Adrover, M, Marcangeli, V, Hammad, R, Granet, J, Gaudreau, P, Aubertin-Leheudre, M, Bélanger, M, Robitaille, R, Deshmukh, AS & Ochala, J 2025, 'Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus', Diabetologia, vol. 68, no. 8, pp. 1836-1850. https://doi.org/10.1007/s00125-025-06436-0

TY - JOUR

T1 - Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus

AU - Lewis, Christopher T.A.

AU - Moreno-Justicia, Roger

AU - Savoure, Lola

AU - Calvo, Enrique

AU - Bak, Agata

AU - Laitila, Jenni

AU - Seaborne, Robert A.E.

AU - Larsen, Steen

AU - Iwamoto, Hiroyuki

AU - Cefis, Marina

AU - Morais, Jose A.

AU - Gouspillou, Gilles

AU - Alegre-Cebollada, Jorge

AU - Hawke, Thomas J.

AU - Vazquez, Jesús

AU - Adrover, Miquel

AU - Marcangeli, Vincent

AU - Hammad, Rami

AU - Granet, Jordan

AU - Gaudreau, Pierrette

AU - Aubertin-Leheudre, Mylène

AU - Bélanger, Marc

AU - Robitaille, Richard

AU - Deshmukh, Atul S.

AU - Ochala, Julien

PY - 2025/4/28

Y1 - 2025/4/28

N2 - 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.

AB - 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.

KW - Diabetes

KW - Metabolism

KW - Myosin

KW - Skeletal muscle

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U2 - 10.1007/s00125-025-06436-0

DO - 10.1007/s00125-025-06436-0

M3 - Article

AN - SCOPUS:105003749906

SN - 0012-186X

VL - 68

SP - 1836

EP - 1850

JO - Diabetologia

JF - Diabetologia

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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