# Spatial proteomics reveals recombinant human laminin-111 restores adhesion signaling to laminin-α2–deficient muscle

## TL;DR

A study shows that treating a severe muscle disease with a specific protein helps restore muscle function and signaling.

## Contribution

The study demonstrates that recombinant human laminin-111 can restore adhesion and signaling in laminin-α2–deficient muscle.

## Key findings

- Loss of heat shock proteins and signaling molecules was observed in laminin-α2–deficient muscle.
- Treatment with recombinant human laminin-111 restored protein localization and reduced ROS.
- Laminin-111 promoted glycolytic and prosurvival signaling in dystrophic muscle.

## 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 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 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, prosurvival 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.

Laminin-α2-related congenital muscular dystrophy is a fatal neuromuscular disorder. Spatial-omics revealed that recombinant human laminin-111 treatment rescued signaling complexes in laminin-α2 deficient muscle.