# Extracellular mitochondria in Inclusion Body Myositis

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2021 · $463,425

## Abstract

Summary
Inclusion body myositis (IBM) is an untreatable inflammatory myopathy of unclear pathogenesis.
Mitochondrial abnormalities are frequently seen in IBM, likely contributing to the muscle weakness. One
prominent feature is the absence of mitochondria in some of the muscle fibers, associated with local
inflammation. However, it is not known why the mitochondria are absent, and how they may contribute to
inflammation. We recently found that mitochondria can be extruded from cells, contributing to inflammation
through the cGAS/STING pathway. Our central hypothesis is that IBM patients have mitochondrial
extrusion from muscle cells resulting in elevated levels of extracellular mitochondria promoting inflammation
and organ damage. To investigate this biology, we have two specific aims. For the first aim, we will
determine whether IBM patients have extracellular mitochondria in circulation, as well as their clinical
significance. We will assess a large variety of mitochondrial components, including mitochondrial (mt) DNA,
oxidized (8-OHdG) DNA, N-formyl-methionine peptides (fMET), as well as mitochondrial protein MT-ND6,
by qPCR and ELISA respectively in well-characterized patients with IBM (n=50), disease controls (n=50),
and healthy individuals (n=50). Mitochondrial markers will be associated with markers of disease activity
and severity. Using a longitudinal cohort (n=40, 10 years follow-up), we aim to determine whether
mitochondrial markers can predict disease progression. To add mechanistic insight into how extracellular
mitochondria may promote inflammation and damage in IBM, neutrophils will be incubated with inhibitors of
known receptors of mtDNA (cGAS, TLR9) and fMET (FPR1) prior to addition of IBM sera containing
mitochondrial components. Outcome measures will include ROS production and degranulation. The second
aim will investigate whether IBM patients have anti-mitochondrial antibodies. We have developed a novel
flow cytometry-based assay to quantify binding of anti-mitochondrial antibodies (AMAs) to the membrane of
mitochondria. Reactivity towards mitochondria will also be assessed by Western blot. The identity of the
mitochondrial autoantigen(s) will be defined using in-gel digestion and subsequent mass spectrometry.
Finally, we will investigate whether AMAs may opsonize mitochondria enhancing their inflammatory
properties. At the completion of this proposed research, our expected outcomes are to have advanced the
understanding of mitochondrial involvement in IBM by providing evidence for mitochondrial extrusion and
novel AMAs (aspects which have not been studied so far). We also expect to have demonstrated potential
therapeutic targets to regulate mitochondrial-mediated inflammation in IBM ensuing muscle damage. We
expect this work to have a positive impact because it will offer novel biomarkers for assessment of disease
progression, as well as identify targetable pathways to limit inflammation and tissue damage in IBM.

## Key facts

- **NIH application ID:** 10282390
- **Project number:** 1R21AR079542-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jan Christian Lood
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,425
- **Award type:** 1
- **Project period:** 2021-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10282390

## Citation

> US National Institutes of Health, RePORTER application 10282390, Extracellular mitochondria in Inclusion Body Myositis (1R21AR079542-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10282390. Licensed CC0.

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