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

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,...

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Detalles Bibliográficos
Autores: Lewis, Christopher T A, Moreno-Justicia, Roger, Savoure, Lola, Calvo, Enrique, Bak, Agata, Laitila, Jenni, Seaborne, Robert A E, Larsen, Steen, Iwamoto, Hiroyuki, Cefis, Marina, Morais, Jose A, Gouspillou, Gilles, Alegre-Cebollada, Jorge, Hawke, Thomas J, Vazquez, Jesús, Adrover, Miquel, Marcangeli, Vincent, Hammad, Rami, Granet, Jordan, Gaudreau, Pierrette, Aubertin-Leheudre, Mylène, Bélanger, Marc, Robitaille, Richard, Deshmukh, Atul S, Ochala, Julien
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26846
Acceso en línea:https://hdl.handle.net/20.500.12105/26846
Access Level:acceso abierto
Palabra clave:Diabetes
Metabolism
Myosin
Skeletal muscle
Descripción
Sumario: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. 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. 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. 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. The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.

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