Characterization of Heterogeneity in Muscle Fiber Types and Selective Susceptibility in Inclusion Body Myositis

With advancing age, the incidence of inflammatory myopathies gradually increases, among which inclusion body myositis (IBM) is the most common type, currently lacking effective treatment methods. Unlike other inflammatory myopathies, IBM presents a chronic course with both inflammatory and degenerative pathological features. Further complicating matters, the factors and molecular drivers behind IBM progression remain unclear. To delve deeper into this disease, researchers used single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics to map cell type-specific drivers in patients’ muscle biopsy samples, aiming to compare IBM muscle with immune-mediated necrotizing myopathy (IMNM) and non-inflammatory skeletal muscle samples.

Research Background and Objectives

IBM is the most prevalent inflammatory myopathy affecting the elderly, resulting in gradual muscle function loss due to the combined effects of immune response and degenerative changes in muscle fibers. However, the molecular mechanisms leading to IBM are not well understood. This study aims to reveal the causes of IBM using novel technological approaches and to provide a scientific basis for future therapeutic strategies.

Research Origin

This research was conducted by a multi-institution team led by Thomas Lloyd and Lucas Schirmer, including contributions from Baylor College of Medicine in the United States and the Medical Faculty of Heidelberg University in Germany. The findings were published in the July 2024 issue of Nature Aging (Volume 4) and are available online at https://doi.org/10.1038/s43587-024-00645-9.

Research Process Details

The researchers employed paired single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics (ST) methods to comprehensively analyze cell types within specific muscle environments during inflammatory and degenerative pathological processes. By mapping each major cell type and its transcriptional characteristics in the samples, the researchers discovered a selective loss of type II muscle nuclei in IBM patients, accompanied by an increase in levels of cytotoxic T cells and conventional type I dendritic cells.

Major Results

Cell type analysis revealed an enrichment of inflammatory gene sets in type I and impaired muscle nuclei subpopulations. Specifically, the study identified a unique, damaged muscle nuclei subpopulation associated with type II muscle fibers, expressing pathological markers such as GADD45A and long non-coding RNA NORAD. Additionally, selective upregulation of the ACHE gene, which is involved in functional denervation of muscle fibers, was observed.

Research Conclusions and Significance

This study is the first to reveal the association between genomic stress pathways and functional denervation in specific muscle fibers and points out the selective susceptibility of type II muscle fibers in IBM. This provides new insights into understanding the molecular pathological mechanisms of IBM and offers a new perspective for the development of future therapeutic strategies. Moreover, the study emphasizes the necessity of further validation of the discovered molecular mechanisms in the progression of IBM pathology.

Research Highlights and Special Notes

• The study combined snRNA-seq and ST to explore patient muscle cell type-specific drivers innovatively.
• It provided insights into the susceptibility of muscle fibers and their link to genomic stress in IBM patients.
• It identified a potential link between the selective upregulation of the ACHE gene and functional denervation in IBM muscle fibers.