iScience
Volume 26, Issue 1, 20 January 2023, 105775
Journal home page for iScience

Article
Diverse effector and regulatory functions of fibro/adipogenic progenitors during skeletal muscle fibrosis in muscular dystrophy

https://doi.org/10.1016/j.isci.2022.105775Get rights and content
Under a Creative Commons license
open access

Highlights

  • scRNAseq supports the effector and regulatory functions of FAPs in muscle fibrosis

  • FAPs are more abundant in the diaphragm than in quadriceps

  • Diaphragm and quadriceps FAPs contain different clusters in the steady state

  • Diaphragm and quadriceps FAPs respond differently to muscular dystrophy

Summary

Fibrosis is a prominent pathological feature of skeletal muscle in Duchenne muscular dystrophy (DMD). The commonly used disease mouse model, mdx5cv, displays progressive fibrosis in the diaphragm but not limb muscles. We use single-cell RNA sequencing to determine the cellular expression of the genes involved in extracellular matrix (ECM) production and degradation in the mdx5cv diaphragm and quadriceps. We find that fibro/adipogenic progenitors (FAPs) are not only the primary source of ECM but also the predominant cells that express important ECM regulatory genes, including Ccn2, Ltbp4, Mmp2, Mmp14, Timp1, Timp2, and Loxs. The effector and regulatory functions are exerted by diverse FAP clusters which are different between diaphragm and quadriceps, indicating their activation by different tissue microenvironments. FAPs are more abundant in diaphragm than in quadriceps. Our findings suggest that the development of anti-fibrotic therapy for DMD should target not only the ECM production but also the pro-fibrogenic regulatory functions of FAPs.

Subject areas

Musculoskeletal medicine
Genetics

Data and code availability

Single-cell based RNA sequencing (scRNAseq) data have been deposited to GEO repository (GEO: GSE218201) and are publicly available as of the date of publication. The accession number is also listed in the key resources table. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

3

These authors contributed equally

4

Lead contact