Muscle regeneration can be rescued in a telomerase deficient zebrafish model of ageing by MMP inhibition

Abstract

Ageing progressively impairs skeletal muscle regeneration, contributing to reduced mobility and quality of life in the ageing population. Whilst the molecular changes underlying muscle ageing have been well characterised, their impact on muscle stem cell (muSC) behaviour during regeneration remains poorly understood. Here, we leverage the telomerase-deficient tert mutant zebrafish larvae as an in vivo model of accelerated ageing to perform real-time analysis of muSC dynamics following muscle injury. We demonstrate that the ageing-like inflammatory environment in tert mutant disrupts muSC migration, impairs activation and proliferation, and compromises regenerative capacity. We further show that sustained inflammation, mediated by persistent macrophage presence and elevated matrix metalloproteinase (MMP) activity directly limits muSC recruitment and migration efficiency. Pharmacological inhibition of MMP9/13 activity and genetic depletion of macrophages partially restore muSC migratory behaviour and regenerative outcomes. Notably, we demonstrate that muSC migration dynamics correlate with regenerative success, providing a functional readout for therapeutic screening. Our findings reveal zebrafish tert mutants offer a tractable system for dissecting age-associated changes to cell behaviour and for identifying rejuvenation interventions.