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
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetologia. 2025 Apr 28. doi: 10.1007/s00125-025-06436-0.
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.
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.
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.
The raw MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD053022.
目的/假设：能量平衡紊乱对2型糖尿病的发生和发展至关重要。对确切的潜在代谢机制的理解仍不完整，但骨骼肌被认为起着重要的致病作用。由于其最丰富的蛋白质肌球蛋白的超松弛状态调节细胞能量代谢，我们旨在研究2型糖尿病患者中该状态是否发生改变。
我们使用了外侧股四头肌活检标本（取自2型糖尿病患者和具有相似特征的对照参与者），并在分离的肌纤维中进行了一系列结构和功能分析，包括负载2'-（或3'）-O-（N-甲基邻氨基苯甲酰基）-ATP（Mant-ATP）追踪实验、X射线衍射和液相色谱-串联质谱蛋白质组学。
我们的研究表明，与对照参与者相比，2型糖尿病男性参与者的肌肉肌球蛋白超松弛程度更高，ATP需求降低。随后的蛋白质组学分析表明，这些（不良）适应可能源于患者的肌节蛋白重塑和肌球蛋白糖基化水平高于对照参与者。
结论/解读：总体而言，我们的研究结果表明2型糖尿病男性参与者的肌球蛋白超松弛状态和能量消耗存在复杂的分子失调。最终，针对肌球蛋白的药物靶向治疗可能通过增加ATP消耗而有益于骨骼肌和全身代谢健康。
原始质谱数据已通过PRIDE合作伙伴存储库存入蛋白质组交换联盟，数据集标识符为PXD053022。
