Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

Martins, S. G.; Ribeiro, V.; Melo, C.; Paulino-Cavaco, C.; Antonini, D.; Dayalan Naidu, S.; Murtinheira, F.; Fonseca, I.; Saget, B.; Pita, M.; Fernandes, D. R.; dos Santos, P. G.; Rodrigues, G.; Zilhao, R.; Herrera, F.; Dinkova-Kostova, A. T.; Carlos, A. R.; Thorsteinsdottir, S.

doi:10.1101/2024.01.20.576409

bioRxiv · 10.1101/2024.01.20.576409

Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy

Martins, S. G.·Ribeiro, V.·Melo, C.·Paulino-Cavaco, C.·Antonini, D.·Dayalan Naidu, S.·Murtinheira, F.·Fonseca, I.·Saget, B.·Pita, M.·Fernandes, D. R.·dos Santos, P. G.·Rodrigues, G.·Zilhao, R.·Herrera, F.·Dinkova-Kostova, A. T.·Carlos, A. R.·Thorsteinsdottir, S.

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Abstract

LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy. This often-lethal disease is triggered by mutations in LAMA2, coding for laminin-2 chain, a key extracellular matrix (ECM) component, prevalent in the skeletal muscle. Several phenotypes have been associated with LAMA2-CMD, however, it is not yet known what mechanisms are faulty, right at disease onset in utero. Using the dyW mouse model of LAMA2-CMD we showed that the disease onset is characterized by a profound downregulation of gene expression, with a marked effect on cytoskeletal organization, myoblast differentiation and fusion and altered DNA repair and oxidative stress responses. Concordantly, we found that Lama2-deficient myoblast cells displayed proliferation and differentiation defects, increased oxidative stress and DNA damage. Together, our findings provide unique insights into the processes dependent on laminin-2 chain during muscle development, revealing its critical importance to maintain muscle cell homeostasis already at fetal stages.

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Martins, S. G., Ribeiro, V., Melo, C., Paulino-Cavaco, C., Antonini, D., Dayalan Naidu, S., Murtinheira, F., Fonseca, I., Saget, B., Pita, M., Fernandes, D. R., dos Santos, P. G., Rodrigues, G., Zilhao, R., Herrera, F., Dinkova-Kostova, A. T., Carlos, A. R., Thorsteinsdottir, S.. 2024-01-24. Deregulation of multiple mechanisms shapes the onset of LAMA2-congenital muscular dystrophy. https://doi.org/10.1101/2024.01.20.576409

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