Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remai...

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Autores: Calls-Cobos A, Beà Tàrrega A, Cisneros A, Rommelfanger M, Campanario S, Grima-Terrén M, Ramírez-Pardo I, Moiseeva V, Lukesova V, Andrés E, Chou G, Zheng Y, Hah N, Blasco-Roset A, Planavila A, Soler-Botija C, Bayés-Genís A, Perdiguero E, Serrano AL, Muñoz-Cánoves P
Tipo de recurso: artículo
Fecha de publicación:2026
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:dnet:r-fsjd______::ecba9b0c8e47a4811cc7dca2700ca4e8
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=30375
Access Level:acceso abierto
Palabra clave:Cardiac remodeling
Cardiomyopathy
Cellular senescence
Dasatinib and quercetin
Duchenne muscular dystrophy
Fibrosis
Mouse models
Preclinical research
Senolytic therapy
Skeletal muscle regeneration
Therapeutic timing
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spelling Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.Calls-Cobos ABeà Tàrrega ACisneros ARommelfanger MCampanario SGrima-Terrén MRamírez-Pardo IMoiseeva VLukesova VAndrés EChou GZheng YHah NBlasco-Roset APlanavila ASoler-Botija CBayés-Genís APerdiguero ESerrano ALMuñoz-Cánoves PCardiac remodelingCardiomyopathyCellular senescenceDasatinib and quercetinDuchenne muscular dystrophyFibrosisMouse modelsPreclinical researchSenolytic therapySkeletal muscle regenerationTherapeutic timingBACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remain unclear. METHODS: We analyzed senescent cell burden in skeletal and cardiac muscles of the DBA/2-mdx mouse model, which closely mimics features of human DMD. The senolytic combination of dasatinib and quercetin (D + Q) was administered during early or late disease phases to evaluate the impact of senescent cell clearance. Skeletal muscle strength was measured by grip strength and ex vivo force assays, while cardiac function was assessed by echocardiography. Fibrosis and senescence markers were quantified histologically, and transcriptional changes associated with senolysis were identified using bulk RNA sequencing (RNA-seq). RESULTS: In skeletal muscle, senescent cells appear and peak during early stages of disease progression (3-5 months), coinciding with high degeneration and regeneration activity, and then decline with age as fibrosis increases. In contrast, in the heart, senescent cells emerge at late stages of disease progression (around 12 months), correlating with heart fibrogenesis. Notably, senolytic intervention in the DBA/2-mdx mice promotes a regenerative and antifibrotic gene signature in both tissues. However, the timing of senolytic therapy determines its efficacy: early treatment with D + Q reduces senescent cell burden, decreases fibrosis, and improves fiber size and contractile performance in skeletal muscle, while later treatment reduces cardiac senescence and fibrosis but does not improve skeletal muscle pathology. CONCLUSIONS: Cellular senescence is a dynamic and targetable feature in DMD, with tissue- and age-specific patterns. It represents a potential modifiable therapeutic target, and temporally optimized senolytic strategies could serve as effective adjuncts to current and emerging DMD treatments.BMC2026info:eu-repo/semantics/articleaheadOfPrintVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=30375Skeletal MuscleISSN: 20445040reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:dnet:r-fsjd______::ecba9b0c8e47a4811cc7dca2700ca4e82026-05-27T12:37:41Z
dc.title.none.fl_str_mv Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
title Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
spellingShingle Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
Calls-Cobos A
Cardiac remodeling
Cardiomyopathy
Cellular senescence
Dasatinib and quercetin
Duchenne muscular dystrophy
Fibrosis
Mouse models
Preclinical research
Senolytic therapy
Skeletal muscle regeneration
Therapeutic timing
title_short Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
title_full Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
title_fullStr Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
title_full_unstemmed Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
title_sort Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
dc.creator.none.fl_str_mv Calls-Cobos A
Beà Tàrrega A
Cisneros A
Rommelfanger M
Campanario S
Grima-Terrén M
Ramírez-Pardo I
Moiseeva V
Lukesova V
Andrés E
Chou G
Zheng Y
Hah N
Blasco-Roset A
Planavila A
Soler-Botija C
Bayés-Genís A
Perdiguero E
Serrano AL
Muñoz-Cánoves P
author Calls-Cobos A
author_facet Calls-Cobos A
Beà Tàrrega A
Cisneros A
Rommelfanger M
Campanario S
Grima-Terrén M
Ramírez-Pardo I
Moiseeva V
Lukesova V
Andrés E
Chou G
Zheng Y
Hah N
Blasco-Roset A
Planavila A
Soler-Botija C
Bayés-Genís A
Perdiguero E
Serrano AL
Muñoz-Cánoves P
author_role author
author2 Beà Tàrrega A
Cisneros A
Rommelfanger M
Campanario S
Grima-Terrén M
Ramírez-Pardo I
Moiseeva V
Lukesova V
Andrés E
Chou G
Zheng Y
Hah N
Blasco-Roset A
Planavila A
Soler-Botija C
Bayés-Genís A
Perdiguero E
Serrano AL
Muñoz-Cánoves P
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cardiac remodeling
Cardiomyopathy
Cellular senescence
Dasatinib and quercetin
Duchenne muscular dystrophy
Fibrosis
Mouse models
Preclinical research
Senolytic therapy
Skeletal muscle regeneration
Therapeutic timing
topic Cardiac remodeling
Cardiomyopathy
Cellular senescence
Dasatinib and quercetin
Duchenne muscular dystrophy
Fibrosis
Mouse models
Preclinical research
Senolytic therapy
Skeletal muscle regeneration
Therapeutic timing
description BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remain unclear. METHODS: We analyzed senescent cell burden in skeletal and cardiac muscles of the DBA/2-mdx mouse model, which closely mimics features of human DMD. The senolytic combination of dasatinib and quercetin (D + Q) was administered during early or late disease phases to evaluate the impact of senescent cell clearance. Skeletal muscle strength was measured by grip strength and ex vivo force assays, while cardiac function was assessed by echocardiography. Fibrosis and senescence markers were quantified histologically, and transcriptional changes associated with senolysis were identified using bulk RNA sequencing (RNA-seq). RESULTS: In skeletal muscle, senescent cells appear and peak during early stages of disease progression (3-5 months), coinciding with high degeneration and regeneration activity, and then decline with age as fibrosis increases. In contrast, in the heart, senescent cells emerge at late stages of disease progression (around 12 months), correlating with heart fibrogenesis. Notably, senolytic intervention in the DBA/2-mdx mice promotes a regenerative and antifibrotic gene signature in both tissues. However, the timing of senolytic therapy determines its efficacy: early treatment with D + Q reduces senescent cell burden, decreases fibrosis, and improves fiber size and contractile performance in skeletal muscle, while later treatment reduces cardiac senescence and fibrosis but does not improve skeletal muscle pathology. CONCLUSIONS: Cellular senescence is a dynamic and targetable feature in DMD, with tissue- and age-specific patterns. It represents a potential modifiable therapeutic target, and temporally optimized senolytic strategies could serve as effective adjuncts to current and emerging DMD treatments.
publishDate 2026
dc.date.none.fl_str_mv 2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
aheadOfPrintVersion
format article
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=30375
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=30375
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Skeletal Muscle
ISSN: 20445040
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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