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Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice
Aina Calls-Cobos1,2, Aida Beà Tàrrega1,2, Andrés Cisneros1,2
1Altos Labs, San Diego Institue of Science, San Diego, USA.
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.
Insights
Cellular senescence drives Duchenne muscular dystrophy (DMD) muscle damage. Senolytic therapy timing is crucial, with early intervention improving skeletal muscle function and late intervention benefiting cardiac health.
Area of Science:
- Biomedical Science
- Cellular Biology
- Musculoskeletal Research
Background:
- Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration, inflammation, and fibrosis.
- Cellular senescence is implicated in chronic muscle damage in DMD, but its role and therapeutic potential are not fully understood.
Purpose of the Study:
- To investigate the temporal dynamics of cellular senescence in DMD.
- To evaluate the efficacy of senolytic therapy in a mouse model of DMD.
Main Methods:
- Analyzed senescent cell burden in skeletal and cardiac muscles of DBA/2-mdx mice.
- Administered dasatinib and quercetin (D+Q) senolytics during early or late disease stages.
- Assessed muscle strength, cardiac function, fibrosis, and gene expression changes.
Main Results:
- Senescent cells peaked early in skeletal muscle and late in cardiac muscle.
- Early D+Q treatment improved skeletal muscle strength, reduced fibrosis, and enhanced fiber size.
- Late D+Q treatment reduced cardiac senescence and fibrosis but did not improve skeletal muscle pathology.
Conclusions:
- Cellular senescence is a dynamic, targetable feature in DMD with tissue- and age-specific patterns.
- Temporally optimized senolytic strategies may complement existing DMD treatments.
