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

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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.

authors

  • Lewis, Christopher TA
  • Moreno-Justicia, Roger
  • Savoure, Lola
  • Calvo, Enrique
  • Bak, Agata
  • Laitila, Jenni
  • Seaborne, Robert AE
  • Larsen, Steen
  • Iwamoto, Hiroyuki
  • Cefis, Marina
  • Morais, Jose A
  • Gouspillou, Gilles
  • Alegre-Cebollada, Jorge
  • Hawke, Thomas
  • Vazquez, Jesús
  • Adrover, Miquel
  • Marcangeli, Vincent
  • Hammad, Rami
  • Granet, Jordan
  • Gaudreau, Pierrette
  • Aubertin-Leheudre, Mylène
  • Bélanger, Marc
  • Robitaille, Richard
  • Deshmukh, Atul S
  • Ochala, Julien

publication date

  • April 28, 2025