Loss of cell-autonomously secreted laminin-α2 drives muscle stem cell dysfunction in LAMA2-related muscular dystrophy

Timothy J. McGowan, Judith R. Reinhard, Nicolas Lewerenz, Marta Białobrzeska, Shuo Lin, Jacek Stępniewski, Krzysztof Szade, Józef Dulak and Markus A. Rüegg ()
Additional contact information
Timothy J. McGowan: University of Basel, Biozentrum
Judith R. Reinhard: University of Basel, Biozentrum
Nicolas Lewerenz: University of Basel, Biozentrum
Marta Białobrzeska: Jagiellonian University, Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology
Shuo Lin: University of Basel, Biozentrum
Jacek Stępniewski: Jagiellonian University, Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology
Krzysztof Szade: Jagiellonian University, Laboratory of Stem Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology
Józef Dulak: Jagiellonian University, Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology
Markus A. Rüegg: University of Basel, Biozentrum

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract The extracellular matrix protein laminin-α2 is essential for preserving the integrity of skeletal muscle fibers during contraction. Its importance is reflected by the severe, congenital LAMA2-related muscular dystrophy (LAMA2 MD) caused by loss-of-function mutations in the LAMA2 gene. While laminin-α2 has an established role in structurally supporting muscle fibers, it remains unclear whether it exerts additional functions that contribute to the maintenance of skeletal muscle integrity. Here, we report that in healthy muscle, activated muscle stem cells (MuSCs) express Lama2 and remodel their microenvironment with laminin-α2. By characterizing LAMA2 MD-afflicted MuSCs and generating MuSC-specific Lama2 knockouts, we show that MuSC-derived laminin-α2 is essential for rapid MuSC expansion and regeneration. In humans, we identify LAMA2 expression in MuSCs and demonstrate that loss-of-function mutations impair cell-cycle progression of myogenic precursors. In summary, we show that self-secreted laminin-α2 supports MuSC proliferation post-injury, thus implicating MuSC dysfunction in LAMA2 MD pathology.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65703-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65703-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65703-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().