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Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy

Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotoni...

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Autores principales: Oliveira-Santos, Ariany, Dagda, Marisela, Wittmann, Jennifer, Smalley, Robert, Burkin, Dean J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184677/
https://www.ncbi.nlm.nih.gov/pubmed/37021539
http://dx.doi.org/10.1242/dmm.049916
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author Oliveira-Santos, Ariany
Dagda, Marisela
Wittmann, Jennifer
Smalley, Robert
Burkin, Dean J.
author_facet Oliveira-Santos, Ariany
Dagda, Marisela
Wittmann, Jennifer
Smalley, Robert
Burkin, Dean J.
author_sort Oliveira-Santos, Ariany
collection PubMed
description Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival and fibrosis have been shown to be dysregulated in LAMA2-CMD. As vemurafenib is a US Food and Drug Administration (FDA)-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dy(W−/−) mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dy(W−/−) mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.
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spelling pubmed-101846772023-05-16 Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy Oliveira-Santos, Ariany Dagda, Marisela Wittmann, Jennifer Smalley, Robert Burkin, Dean J. Dis Model Mech Research Article Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival and fibrosis have been shown to be dysregulated in LAMA2-CMD. As vemurafenib is a US Food and Drug Administration (FDA)-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dy(W−/−) mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dy(W−/−) mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD. The Company of Biologists Ltd 2023-05-10 /pmc/articles/PMC10184677/ /pubmed/37021539 http://dx.doi.org/10.1242/dmm.049916 Text en © 2023. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Oliveira-Santos, Ariany
Dagda, Marisela
Wittmann, Jennifer
Smalley, Robert
Burkin, Dean J.
Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy
title Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy
title_full Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy
title_fullStr Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy
title_full_unstemmed Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy
title_short Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy
title_sort vemurafenib improves muscle histopathology in a mouse model of lama2-related congenital muscular dystrophy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184677/
https://www.ncbi.nlm.nih.gov/pubmed/37021539
http://dx.doi.org/10.1242/dmm.049916
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