Dysregulated Skeletal Muscle Myosin Super-relaxation in Type II, but Not Type I, Diabetes Mellitus

Lewis, C. T.; Moreno-Justicia, R.; Savoure, L.; Calvo, E.; Bak, A.; Laitila, J.; Seaborne, R. A. E.; Larsen, S.; Iwamoto, H.; Cefis, M.; Morais, J. A.; Gouspilou, G.; Alegre-Cebollada, J.; Hawke, T. J.; Vazquez, J.; Adrover, M.; Marcangeli, V.; Deshmukh, A. S.; Ochala, J.

doi:10.1101/2024.06.12.598615

bioRxiv · 10.1101/2024.06.12.598615

Dysregulated Skeletal Muscle Myosin Super-relaxation in Type II, but Not Type I, Diabetes Mellitus

Lewis, C. T.·Moreno-Justicia, R.·Savoure, L.·Calvo, E.·Bak, A.·Laitila, J.·Seaborne, R. A. E.·Larsen, S.·Iwamoto, H.·Cefis, M.·Morais, J. A.·Gouspilou, G.·Alegre-Cebollada, J.·Hawke, T. J.·Vazquez, J.·Adrover, M.·Marcangeli, V.·Deshmukh, A. S.·Ochala, J.

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Abstract

Disrupted energy balance is critical for the onset and development of Type II diabetes. The exact underlying metabolic mechanisms remain 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, here, we aimed to investigate whether it is altered in patients with type II diabetes. For that, we used vastus lateralis biopsy specimens (obtained from patients with type II diabetes and matched controls) and run a combination of structural and functional assays consisting of loaded 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 cellular ATP demand in patients than controls. Subsequent proteomic analyses indicated that these (mal)adaptations likely originated from remodeled sarcomeric proteins and greater myosin glycation levels in patients than controls. Overall, our findings emphasize a complex molecular dysregulation of myosin super-relaxed state and energy consumption in type II diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through the enhancement of ATP consumption. Significance StatementMyosin super-relaxation, essential for the regulation of skeletal muscle metabolic rate, is disrupted in type II diabetes due to protein hyper-glycation. As a consequence, myosin ATP demand is significantly lowered. Overall, our findings provide a strong rationale for the use of activators of myosin ATPase to enhance basal energy expenditure in type II diabetes.

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Lewis, C. T., Moreno-Justicia, R., Savoure, L., Calvo, E., Bak, A., Laitila, J., Seaborne, R. A. E., Larsen, S., Iwamoto, H., Cefis, M., Morais, J. A., Gouspilou, G., Alegre-Cebollada, J., Hawke, T. J., Vazquez, J., Adrover, M., Marcangeli, V., Deshmukh, A. S., Ochala, J.. 2024-06-13. Dysregulated Skeletal Muscle Myosin Super-relaxation in Type II, but Not Type I, Diabetes Mellitus. https://doi.org/10.1101/2024.06.12.598615

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