Proteomics

Dataset Information

0

A pathogenic role for mitochondrial dysfunction and oxidative stress in myositis


ABSTRACT: Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Quadriceps

SUBMITTER: Clement GUILLOU  

LAB HEAD: ABAD Catalina

PROVIDER: PXD048004 | Pride | 2024-05-31

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
NOD_25W_1.msf Msf
NOD_25W_1.raw Raw
NOD_25W_2.msf Msf
NOD_25W_2.raw Raw
NOD_25W_3.msf Msf
Items per page:
1 - 5 of 60

Similar Datasets

2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress
2024-05-29 | GSE262352 | GEO
2024-05-23 | MTBLS9677 | MetaboLights
2016-08-08 | GSE71501 | GEO
2021-07-21 | GSE178356 | GEO
2020-07-06 | PXD017678 | Pride
2020-07-06 | PXD017621 | Pride
2020-07-06 | PXD017683 | Pride
2023-02-23 | GSE201092 | GEO
2019-11-14 | GSE111016 | GEO