2026-06-14T03:33:54Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/268462025-07-24T00:18:05Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Lewis, Christopher T A author Moreno-Justicia, Roger author Savoure, Lola author Calvo, Enrique author Bak, Agata author Laitila, Jenni author Seaborne, Robert A E author Larsen, Steen author Iwamoto, Hiroyuki author Cefis, Marina author Morais, Jose A author Gouspillou, Gilles author Alegre-Cebollada, Jorge author Hawke, Thomas J author Vazquez, Jesús author Adrover, Miquel author Marcangeli, Vincent author Hammad, Rami author Granet, Jordan author Gaudreau, Pierrette author Aubertin-Leheudre, Mylène author Bélanger, Marc author Robitaille, Richard author Deshmukh, Atul S author Ochala, Julien author 2025-08 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. Diabetologia. 2025 Aug;68(8):1836-1850. Diabetologia 40295335 https://hdl.handle.net/20.500.12105/26846 Diabetes Metabolism Myosin Skeletal muscle Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.