Senescent-like -expressing myofibers may worsen by creating cytokine signals that suppress muscle regeneration.
Evidence
This preclinical DMD rat study combined RNA-seq, blood cytokine profiling, transplanted muscle regeneration assays, p16 ablation, and isolated myofiber analyses.
Caveat
The mechanism is shown in rat muscle and graft models, so its relevance to human DMD progression or treatment remains untested here.
Simplified
(DMD) is a genetic muscular disease characterized by progressive muscle degeneration. is expressed in skeletal muscles and induces cellular senescence in a rat model of DMD, whereas its ablation enhances muscle regeneration. However, the mechanism underlying this phenomenon remains unclear. This study aimed to elucidate the mechanism for p16-induced DMD exacerbation. RNA-seq analysis revealed p16-dependent upregulation of cytokine gene expression in DMD rat skeletal muscles, which also altered the systemic blood cytokine profile. Furthermore, the effect of an altered humoral environment on muscle regeneration was assessed using the transplanted extensor digitorum longus muscle. Regeneration of grafted muscles from wild-type rats was suppressed in DMD rats but was significantly improved by p16 ablation. Notably, p16 was expressed in the myofibers of DMD rats, and enzymatically isolated myofibers from DMD rats also showed p16-dependent cytokine expression. Thus, cytokines secreted by senescent-like myofibers mediate the anti-regenerative niche in DMD rats, uncovering a novel mechanism for disease progression and potential therapeutic targets.
Key numbers
-dependent upregulation
Cytokine Expression Increase
Cytokine levels in rat myofibers are significantly higher than in wild-type.
smaller in rats
Regenerating Myofiber Diameter Decrease
Diameter of regenerating myofibers was lower in rats compared to wild-type or -null rats.
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