Gasdermin E: a missing link in muscle regeneration

Area of Science:

• Muscle regeneration
• Cellular senescence
• Inflammation

Background:

• Skeletal muscle regeneration is impaired by aging and disease.
• The microenvironment's role in muscle repair is complex.
• Gasdermin E (GSDME) function in muscle repair is largely unknown.

Purpose of the Study:

• To investigate the role of GSDME in myeloid cells during skeletal muscle regeneration.
• To determine the impact of GSDME on age-related muscle repair deficits.
• To explore the therapeutic potential of IL-18 in aged muscle regeneration.

Main Methods:

• Genetic mouse models (GSDME knockout).
• Pharmacological interventions.
• Analysis of muscle injury, regeneration, and ectopic fat deposition.
• Assessment of GSDME expression in young and aged human and mouse muscle.

Main Results:

• GSDME in myeloid cells is essential for normal muscle regeneration after sterile injury.
• IL-18, downstream of GSDME, prevents ectopic fat deposition in muscle.
• GSDME expression decreases with age and is reduced after injury in old mice.
• IL-18 partially rescues regeneration in aged GSDME-knockout mice.

Conclusions:

• GSDME-mediated IL-18 release is a key mechanism for effective muscle regeneration.
• Age-related decline in GSDME contributes to impaired muscle repair.
• Targeting the GSDME-IL-18 pathway may represent a therapeutic strategy for age-associated muscle dysfunction.