Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.
Por:
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 and Muñoz-Cánoves P
Publicada:
2 may 2026
Ahead of Print:
2 may 2026
Resumen:
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.
Filiaciones:
Calls-Cobos A:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Beà Tàrrega A:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Cisneros A:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Rommelfanger M:
Altos Labs, San Diego Institue of Science, San Diego, USA
Campanario S:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Grima-Terrén M:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Ramírez-Pardo I:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Moiseeva V:
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Lukesova V:
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Andrés E:
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Chou G:
Altos Labs, San Diego Institue of Science, San Diego, USA
Zheng Y:
Altos Labs, San Diego Institue of Science, San Diego, USA
Hah N:
Altos Labs, San Diego Institue of Science, San Diego, USA
Blasco-Roset A:
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, 08028, Spain
Planavila A:
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, 08028, Spain
Soler-Botija C:
ICREC Research Lab, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
Heart Institute (iCOR), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
Bayés-Genís A:
ICREC Research Lab, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
Heart Institute (iCOR), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain
Perdiguero E:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Serrano AL:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Muñoz-Cánoves P:
Altos Labs, San Diego Institue of Science, San Diego, USA
Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
Open Access
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