# Proteomic profiles in inclusion body myositis and polymyositis with mitochondrial pathology

## TL;DR

This study identifies unique protein patterns in IBM and PM-Mito, suggesting they share molecular features and supporting PM-Mito as an early stage of IBM.

## Contribution

The study reveals distinct proteomic signatures and novel protein markers in IBM and PM-Mito, offering insights into their shared molecular pathways.

## Key findings

- IBM has a distinct proteomic profile marked by upregulated MHC and cytoskeletal proteins.
- PM-Mito shares IBM-like features but preserves type 2 myofiber markers and shows mitochondrial remodeling.
- Transcriptomic validation confirmed key proteomic changes in both IBM and PM-Mito.

## Abstract

Idiopathic inflammatory myopathies (IIMs) are autoimmune muscle diseases with distinct clinical, histopathological, and molecular features. Among them, inclusion body myositis (IBM) is refractory to immunotherapy and characterized by combined inflammatory and degenerative changes. Polymyositis with mitochondrial pathology (PM-Mito) has been proposed as a prodromal stage of IBM, but molecular profile underlying this spectrum remains poorly defined.

Skeletal muscle biopsies from 38 IBM, 14 PM-Mito, 5 anti-synthetase syndrome (ASyS), 3 dermatomyositis (DM), 5 immune-mediated necrotizing myopathy (IMNM), and 7 non-diseased controls (NDC) were analyzed by label-free mass spectrometry and validated by bulk RNA sequencing. Dimensionality reduction was performed using sparse Partial Least Squares Discriminant Analysis (sPLS-DA), followed by differential protein analysis.

IBM exhibited a homogeneous and distinct proteomic signature compared with other IIM subtypes, driven by upregulation of MHC class I (e.g. HLA-A) and II (e.g. HLA-DRB1, CD74) molecules, and cytoskeletal proteins (e.g. PDCL3). Comparing IBM to other types of IIM, we also detected increased level of specific histone variants (e.g. HIST2H2AA3, H1FX). Enrichment analysis of the differential proteins underscored increased antigen presentation and T-cell–mediated immunity pathways, with concomitant depletion of mitochondrial respiratory chain, RNA processing, and oxidative phosphorylation components in IBM. PM-Mito shared a proteomic profile with IBM with reduced MT-ND2 levels and increases in lipid storage regulator PLIN1 and extracellular matrix protein COL14A1, among others. In contrast to IBM, PM-Mito preserved type 2 myofiber markers (e.g. MYH2). A specific protein change to PM-Mito was an increase in the cytochrome c oxidase subunit III (MT-CO3), implicating mitochondrial remodelling. Transcriptomic analysis validated the proteomic changes in COL14A1, IGLL4, PLIN1, MT-ND2, SMDT1, and TIMM21, all of which were shared between IBM and PM-Mito.

IBM exhibits a unique proteomic landscape distinct from other IIMs. The overlap with PM-Mito suggests that these conditions share molecular features, supporting an interpretation that places PM-Mito in the broader spectrum of IBM. Novel protein markers, including histone variants and cytoskeletal regulators, highlight potential pathways for future research. These findings underscore the need for longitudinal studies exploring therapeutic targets in early disease stages.

The online version contains supplementary material available at 10.1186/s40478-026-02243-9.