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

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. Submitted transcriptomic data represents gene expression profile of control and LAMA2-deficient human myogenic precursor cells derived from induced pluripotent stem cells which was analyzed to better understand the role of laminin-α2 in human cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307443 | GEO | 2025/09/14

REPOSITORIES: GEO

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Project description:LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by LAMA2 mutations, leading to muscle degeneration, chronic inflammation, and fibrosis. Histopathological assessment of muscle biopsies from LAMA2-CMD patients and mouse models show clear evidence of inflammation, which oftentimes are regarded as one of the typical dystrophic hallmarks. However, the composition of immune cells in the laminin-deficient muscles remain understood. Consequently, targeted pharmacological intervention to reduce inflammation has never been tested. In this study, we characterized the immune landscape in dyW mouse model of LAMA2-CMD using RNA sequencing and flow cytometry. Transcriptomic analysis of dyW quadriceps identified 2,143 differentially expressed genes, with most of the upregulated genes belong to immune-related pathways. Lgals3 (Galectin-3) was significantly upregulated (log₂FC = 4.27, FDR p-value= 9.21x10-88) and identified as a key upstream regulator of the immune-related pathways. In parallel, flow cytometry analysis revealed elevated leukocyte (CD45⁺) infiltration, with macrophages as the predominant cell population. Pro-inflammatory (M1) macrophages were increased, whereas anti-inflammatory (M2) macrophages remained low, indicating persistent inflammation and impaired resolution. Interestingly, Galectin-3+ macrophages were significantly enriched, which strongly suggest that Galectin-3 drives inflammation in LAMA2-CMD. Treatment of dyW mice with TD-139, a Galectin-3 inhibitor, reduced leukocyte infiltration, decreased Galectin-3+ macrophages, and shifted macrophage polarization toward an M2 anti-inflammatory profile. In addition, RNA sequencing of TD-139-treated dyW muscles showed upregulation of muscle repair pathways and downregulation of fibrosis-related genes. These findings establish Galectin-3-expressing macrophages as an important player in LAMA2-CMD pathophysiology. Importantly, it warrants further investigation on the therapeutic potential of TD-139-mediated inhibition of Galectin-3, including long-term preclinical study, in LAMA2-CMD and potentially other dystrophic conditions driven by chronic immune activation.

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

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