Journal article
Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling to laminin-α2 deficient muscle
JCI insight, Vol.10(22), 194581
11/24/2025
DOI: 10.1172/jci.insight.194581
PMCID: PMC12643501
PMID: 41118381
Abstract
Laminin-α2-related Congenital Muscular Dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by mutations in the LAMA2 gene, leading to loss of heterotrimers laminin-211/221, key components of the skeletal muscle extracellular matrix. Their absence disrupts adhesion between the cytoskeleton and extracellular matrix, resulting in progressive muscle wasting. Laminin-211/221 interacts with adhesion complexes such as the dystrophin/Utrophin glycoprotein complex and the α7β1-integrin. However, the regulatory mechanisms of these laminin-binding complexes and the broader role of laminin's influence on the formation of the macromolecular network in skeletal muscle remain unclear. We previously demonstrated that mouse laminin-111 delivered in the dyW⁻/⁻ mouse model of LAMA2-CMD prevented disease progression, improved strength, and extended survival. We hypothesize that laminin-111, the embryonic laminin isoform, restores key adhesion-signaling networks. Using spatial-proteomics on patient and mouse muscle, we identified loss of essential signaling components: heat shock proteins 27 and 70, c-Jun N-terminal kinase, and glucose transporter 1 in laminin-α2 deficient muscle. Treatment with recombinant human laminin-111 (rhLAM-111) restored protein localization, reduced ROS, and promoted glycolytic, pro-survival signaling. These findings highlight laminin's role in maintaining muscle homeostasis and metabolism and support the therapeutic potential of rhLAM-111 for treating LAMA2-CMD by restoring adhesion and intracellular signaling in dystrophic muscle.
Details
- Title: Subtitle
- Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling to laminin-α2 deficient muscle
- Creators
- Hailey J Hermann - University of Nevada, RenoRyan D Wuebbles - University of Nevada, RenoMarisela Dagda - University of Nevada, RenoAxel Munoz - University of Nevada, RenoLauren L Parker - University of Nevada, RenoPaula C Guzman - University of Nevada, Reno School of MedicineLola T Byrne - University of Nevada, RenoSteven A Moore - University of IowaDean J Burkin - University of Nevada, Reno
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.10(22), 194581
- DOI
- 10.1172/jci.insight.194581
- PMID
- 41118381
- PMCID
- PMC12643501
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- NIH/NINDS: 1R01NS136281-01 Cure CMD: 1018515 University of Iowa Paul D. Wellstone Muscular Dystrophy Specialized Research Center NIH: P50NS053672
This work is the result of NIH/NINDS funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central.center dot NIH/NNDS grant 1R01NS136281-01 to DJB.center dot Cure CMD award 1018515 to DJB.center dot University of Iowa Paul D. Wellstone Muscular Dystrophy Specialized Research Center NIH grant P50NS053672 to SAM.
- Language
- English
- Electronic publication date
- 10/16/2025
- Date published
- 11/24/2025
- Academic Unit
- Pathology
- Record Identifier
- 9985019141602771
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