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

ABSTRACT: Skeletal muscle plays a critical role in the onset and development of type II diabetes. However, very few studies have investigated the potential pathogenic role of its most abundant protein, myosin. Hence, here, we aim to define this by focusing on myosin energy-saving state known as super-relaxed state (SRX). We performed an array of (loaded Mant-ATP chase experiments, LC-MS/MS proteomics, X-ray diffraction) assays on vastus lateralis biopsies from diabetic patients and matched controls. Strikingly, our results highlight that the amount of muscle myosin molecules in SRX is higher and the related ATP demand lower in type II diabetes patients than in controls. These physiological changes are parallel with greater glycation levels on myosin heavy chains, and with remodeled sarcomeric proteins in the same type II diabetes patients. None of these (mal)adaptations were noticed in patients with type I diabetes. Altogether, our findings emphasize a complex molecular dysregulation of myosin SRX and ATP consumption in type II diabetes. Ultimately, pharmacological targeting of SRX could benefit whole-body metabolic health through the enhancement of energy expenditure.

INSTRUMENT(S): timsTOF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle Fiber

DISEASE(S): Type 2 Diabetes Mellitus,Type 1 Diabetes Mellitus

SUBMITTER: Roger Moreno Justicia  

LAB HEAD: Atul Shahaji Deshmukh

PROVIDER: PXD053022 | Pride | 2025-04-29

REPOSITORIES: Pride