Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling and metabolic function to laminin-α2 deficient muscle

Hailey Hermann; Ryan Wuebbles; Marisela Dagda; Axel Munoz; Lauren Parker; Paula Guzman; Lola Byrne; Steven Moore; Dean Burkin

doi:10.5061/dryad.j0zpc86qw

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Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling and metabolic function to laminin-α2 deficient muscle

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Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling and metabolic function to laminin-α2 deficient muscle

Hailey Hermann, Ryan Wuebbles, Marisela Dagda, Axel Munoz, Lauren Parker, Paula Guzman, Lola Byrne, Steven Moore and Dean Burkin

Dryad

01/28/2025

DOI: 10.5061/dryad.j0zpc86qw

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https://doi.org/10.5061/dryad.j0zpc86qwView

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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 complexes and α7β1-integrins. 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 delivering mouse laminin-111 to 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.

Muscular Dystrophy

congenital muscular dystrophy

dyW

FOS: Medical and health sciences

integrin

LAMA-CMD

laminin adhesion complexes

laminin-111

laminin-211

protein therapy

Details

Title: Subtitle: Spatial-proteomics reveals recombinant human laminin-111 restores adhesion-signaling and metabolic function to laminin-α2 deficient muscle
Creators: Hailey Hermann - University of Nevada, Reno School of Medicine
Ryan Wuebbles - University of Nevada, Reno School of Medicine
Marisela Dagda - University of Nevada, Reno School of Medicine
Axel Munoz - University of Nevada, Reno School of Medicine
Lauren Parker - University of Nevada, Reno School of Medicine
Paula Guzman - University of Nevada, Reno School of Medicine
Lola Byrne - University of Nevada, Reno School of Medicine
Steven Moore - University of Iowa
Dean Burkin - University of Nevada, Reno School of Medicine
Resource Type: Dataset
DOI: 10.5061/dryad.j0zpc86qw
Publisher: Dryad
Grant note: 1R01NS136281-01 / National Institute of Neurological Disorders and Stroke (https://ror.org/01s5ya894) 1018515 / Cure CMD (https://ror.org/01thp7c65) P50NS053672 / National Institute of Neurological Disorders and Stroke (https://ror.org/01s5ya894)
Language: English
Date published: 01/28/2025
Academic Unit: Pathology
Record Identifier: 9984969241302771

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