Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms

Susana G Martins; Vanessa Ribeiro; Catarina Melo; Cláudia Paulino-Cavaco; Dario Antonini; Sharadha Dayalan Naidu; Fernanda Murtinheira; Inês Fonseca; Bérénice Saget; Mafalda Pita; Diogo R Fernandes; Pedro Gameiro Dos Santos; Gabriela Rodrigues; Rita Zilhão; Federico Herrera; Albena T Dinkova-Kostova; Ana Rita Carlos; Sólveig Thorsteinsdóttir

doi:10.26508/lsa.202402829

Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms

Susana G Martins, Vanessa Ribeiro, Catarina Melo, Cláudia Paulino-Cavaco, Dario Antonini, Sharadha Dayalan Naidu, Fernanda Murtinheira, Inês Fonseca, Bérénice Saget, Mafalda Pita, Diogo R Fernandes, Pedro Gameiro Dos Santos, Gabriela Rodrigues, Rita Zilhão, Federico Herrera, Albena T Dinkova-Kostova, Ana Rita Carlos (Lead / Corresponding author), Sólveig Thorsteinsdóttir (Lead / Corresponding author)

Cancer Research

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Abstract

LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-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 Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W 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.

Original language	English
Article number	e202402829
Number of pages	23
Journal	Life Science Alliance
Volume	7
Issue number	12
Early online date	8 Oct 2024
DOIs	https://doi.org/10.26508/lsa.202402829
Publication status	Published - Dec 2024

Keywords

Animals
Laminin/metabolism
Mice
Muscle, Skeletal/metabolism
Cell Differentiation/genetics
Myoblasts/metabolism
Oxidative Stress/genetics
DNA Damage
Muscular Dystrophies/metabolism
Cell Proliferation/genetics
Cell Line
Muscle Development/genetics
Disease Models, Animal
Mutation
Muscle Fibers, Skeletal/metabolism
Cell Biology
Development
Physiology

ASJC Scopus subject areas

Ecology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Plant Science
Health, Toxicology and Mutagenesis

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10.26508/lsa.202402829Licence: CC BY

Final published versionFinal published version, 5.26 MBLicence: CC BY

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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., Gameiro Dos Santos, P., Rodrigues, G., Zilhão, R., Herrera, F., Dinkova-Kostova, A. T., Carlos, A. R., & Thorsteinsdóttir, S. (2024). Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms. Life Science Alliance, 7(12), Article e202402829. https://doi.org/10.26508/lsa.202402829

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title = "Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms",

abstract = "LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-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 Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W 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. ",

keywords = "Animals, Laminin/metabolism, Mice, Muscle, Skeletal/metabolism, Cell Differentiation/genetics, Myoblasts/metabolism, Oxidative Stress/genetics, DNA Damage, Muscular Dystrophies/metabolism, Cell Proliferation/genetics, Cell Line, Muscle Development/genetics, Disease Models, Animal, Mutation, Muscle Fibers, Skeletal/metabolism, Cell Biology, Development, Physiology",

author = "Martins, {Susana G} and Vanessa Ribeiro and Catarina Melo and Cl{\'a}udia Paulino-Cavaco and Dario Antonini and {Dayalan Naidu}, Sharadha and Fernanda Murtinheira and In{\^e}s Fonseca and B{\'e}r{\'e}nice Saget and Mafalda Pita and Fernandes, {Diogo R} and {Gameiro Dos Santos}, Pedro and Gabriela Rodrigues and Rita Zilh{\~a}o and Federico Herrera and Dinkova-Kostova, {Albena T} and Carlos, {Ana Rita} and S{\'o}lveig Thorsteinsd{\'o}ttir",

note = "{\textcopyright} 2024 Martins et al.",

year = "2024",

month = dec,

doi = "10.26508/lsa.202402829",

language = "English",

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journal = "Life Science Alliance",

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Martins, SG, Ribeiro, V, Melo, C, Paulino-Cavaco, C, Antonini, D, Dayalan Naidu, S, Murtinheira, F, Fonseca, I, Saget, B, Pita, M, Fernandes, DR, Gameiro Dos Santos, P, Rodrigues, G, Zilhão, R, Herrera, F, Dinkova-Kostova, AT, Carlos, AR & Thorsteinsdóttir, S 2024, 'Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms', Life Science Alliance, vol. 7, no. 12, e202402829. https://doi.org/10.26508/lsa.202402829

TY - JOUR

T1 - Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms

AU - Martins, Susana G

AU - Ribeiro, Vanessa

AU - Melo, Catarina

AU - Paulino-Cavaco, Cláudia

AU - Antonini, Dario

AU - Dayalan Naidu, Sharadha

AU - Murtinheira, Fernanda

AU - Fonseca, Inês

AU - Saget, Bérénice

AU - Pita, Mafalda

AU - Fernandes, Diogo R

AU - Gameiro Dos Santos, Pedro

AU - Rodrigues, Gabriela

AU - Zilhão, Rita

AU - Herrera, Federico

AU - Dinkova-Kostova, Albena T

AU - Carlos, Ana Rita

AU - Thorsteinsdóttir, Sólveig

PY - 2024/12

Y1 - 2024/12

N2 - LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-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 Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W 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.

AB - LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-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 Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W 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.

KW - Animals

KW - Laminin/metabolism

KW - Mice

KW - Muscle, Skeletal/metabolism

KW - Cell Differentiation/genetics

KW - Myoblasts/metabolism

KW - Oxidative Stress/genetics

KW - DNA Damage

KW - Muscular Dystrophies/metabolism

KW - Cell Proliferation/genetics

KW - Cell Line

KW - Muscle Development/genetics

KW - Disease Models, Animal

KW - Mutation

KW - Muscle Fibers, Skeletal/metabolism

KW - Cell Biology

KW - Development

KW - Physiology

UR - http://www.scopus.com/inward/record.url?scp=85206025207&partnerID=8YFLogxK

U2 - 10.26508/lsa.202402829

DO - 10.26508/lsa.202402829

M3 - Article

C2 - 39379105

SN - 2575-1077

VL - 7

JO - Life Science Alliance

JF - Life Science Alliance

IS - 12

M1 - e202402829

ER -

Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms

Abstract

Keywords

ASJC Scopus subject areas

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