Muscle Regeneration Can Be Rescued in a Telomerase Deficient Zebrafish Model of Ageing by MMP Inhibition

Area of Science:

• Muscle regeneration
• Aging biology
• Stem cell dynamics

Background:

• Skeletal muscle regeneration declines with age, impacting mobility.
• Molecular mechanisms of age-related muscle stem cell (muSC) dysfunction are unclear.
• Understanding muSC behavior during aging is crucial for therapeutic development.

Purpose of the Study:

• To investigate the impact of accelerated aging on muSC behavior during muscle regeneration.
• To identify molecular mediators of impaired muSC function in aged muscle.
• To evaluate potential therapeutic interventions for age-related muscle degeneration.

Main Methods:

• Utilized telomerase-deficient tert mutant zebrafish larvae as a model of accelerated aging.
• Performed real-time analysis of muSC dynamics following muscle injury.
• Assessed the role of inflammation, macrophages, and matrix metalloproteinases (MMPs) in muSC function.

Main Results:

• Accelerated aging in tert mutants created an inflammatory environment that disrupted muSC migration, activation, and proliferation.
• Persistent macrophages and elevated MMP activity (MMP9/13) limited muSC recruitment and migration.
• Pharmacological inhibition of MMPs and macrophage depletion partially restored muSC migration and regenerative capacity.
• muSC migration dynamics were found to correlate with regenerative success.

Conclusions:

• Zebrafish tert mutants provide a valuable in vivo model for studying age-related cellular changes.
• Sustained inflammation and MMP activity are key contributors to impaired muscle regeneration in aging.
• Targeting inflammation and MMPs shows promise for rejuvenating muscle stem cell function and enhancing regenerative outcomes.