Laminin-α2 deficiency is associated with altered multiorgan redox signatures.

Muscle diseases often involve redox imbalance, driven by elevated ROS levels, impaired antioxidant defenses, mitochondrial dysfunction, and metabolic rewiring. In several muscular dystrophies caused by extracellular matrix gene mutations, increased oxidative stress in skeletal muscle is a defining feature. One such condition is LAMA2-congenital muscular dystrophy (LAMA2-CMD), resulting from mutations in LAMA2, which encodes the laminin-α2 chain. Although oxidative stress has been implicated in the muscle pathology in LAMA2-CMD, whether this effect extends beyond skeletal muscle remains unclear. Here, we used the dyW mouse model for LAMA2-CMD, which exhibits well-established muscle defects beginning at fetal stages, to investigate whether pathology is also present in other organs at disease onset. We found that Lama2-deficiency alters antioxidant responses in the fetal heart, kidney, and liver, with all three organs displaying increased NRF2 protein levels accompanied by organ-specific changes in selected NRF2 target genes. This phenotype is associated with alterations in mitochondrial markers in the kidney, not evident in the heart or the liver. To further understand the kidney phenotype, we isolated Lama2-deficient proximal tubule epithelial cells from fetal kidneys, which displayed defects in proliferation and mitochondrial metabolism in vitro, indicating a cell-autonomous effect. However, alterations in the NRF2 pathway were not detected, suggesting that its regulation may depend on the in vivo tissue context. Overall, this study provides the first evidence supporting a multi-organ involvement in laminin-α2 chain deficiency from the earliest stages of disease, extending the known phenotype beyond skeletal muscle. It further underscores the importance of laminin-α2 chain in maintaining tissue homeostasis and redox balance, offering new insights into systemic aspects of LAMA2-CMD.