Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms
LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in <i>LAMA2</i> trigger the often-lethal <i>LAMA2</i>-congenital muscular dystrophy (LAMA2-CMD). Various phenotypes have been linked to LAMA2-CMD; nevertheless, the precise mechanisms that malfunction during disease onset in utero remain unknown. We generated <i>Lama2</i>-deficient C2C12 cells and found that <i>Lama2</i>-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the <i>dy</i> <sup><i>W</i></sup> mouse model of LAMA2-CMD display impaired differentiation and fusion in vitro. We also showed that disease onset during fetal development is characterized by a significant down-regulation of gene expression in muscle fibers, causing pronounced effects on cytoskeletal organization, muscle differentiation, and altered DNA repair and oxidative stress responses. Together, our findings provide unique insights into the critical importance of the laminin-α2 chain for muscle differentiation and muscle cell homeostasis.
Authors
- Pedro Gameiro dos Santos (ORCID: https://orcid.org/0000-0003-3829-4019)
- Ana Rita Carlos (ORCID: https://orcid.org/0000-0002-6953-1163)
- Fernanda Murtinheira (ORCID: https://orcid.org/0000-0002-5096-5631)
- Catarina Drumonde Melo (ORCID: https://orcid.org/0000-0003-0691-6725)
- Sharadha Dayalan Naidu (ORCID: https://orcid.org/0000-0002-7692-5611)
- Dario Antonini (ORCID: https://orcid.org/0000-0002-3200-5119)
- Sólveig Þorsteinsdóttir (ORCID: https://orcid.org/0000-0002-9018-3431)
- Mafalda Pita (ORCID: https://orcid.org/0009-0008-8848-5917)
- Gabriela Rodrigues (ORCID: https://orcid.org/0000-0002-0598-4040)
- Vanessa Ribeiro (ORCID: https://orcid.org/0000-0003-3267-3157)
- Albena T. Dinkova‐Kostova (ORCID: https://orcid.org/0000-0003-0316-9859)
- Rita Zilhão (ORCID: https://orcid.org/0000-0002-1885-5432)
- Federico Herrera (ORCID: https://orcid.org/0000-0002-9596-9353)
- Susana G. Martins
- Cláudia Paulino-Cavaco
- Bérénice Saget
- I. T. E. Fonseca (ORCID: https://orcid.org/0009-0000-6330-4667)
- Diogo R Fernandes
Institutions
- University of Lisbon (PT)
- University of Dundee (GB)
- Center for Health and Gender Equity (US)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2024-10-08
- DOI
- https://doi.org/10.26508/lsa.202402829
- Citations
- 9
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- Association Française contre les Myopathies
- European Cooperation in Science and Technology
- Universidade de Lisboa
- Fundação para a Ciência e a Tecnologia
- European Regional Development Fund