Enhancer Rewiring Orchestrates Inflammation and Loss of Cell Identity During Muscle Stem Cell Aging

Area of Science:

• Gerontology and Regenerative Medicine
• Molecular Biology and Genomics
• Stem Cell Biology

Background:

• Organ regeneration declines with age, often due to stem cell exhaustion.
• Skeletal muscle stem cells (MuSCs) show age-related loss in number and function, impairing muscle repair.
• Understanding these age-related changes is crucial for developing interventions to restore muscle regenerative capacity.

Purpose of the Study:

• To systematically profile the epigenome, transcriptome, and 3D genome of individual mouse MuSCs across different age groups and sexes.
• To identify molecular alterations in MuSCs that occur progressively during aging.
• To correlate these molecular changes with functional deficits in muscle regeneration.

Main Methods:

• Utilized low-input multi-omics techniques to analyze individual MuSCs.
• Compared young, old, and geriatric mice of both sexes.
• Integrated epigenomic, transcriptomic, and 3D genome data to provide a comprehensive view of MuSC aging.

Main Results:

• Young male MuSCs exhibited reduced cell cycle gene expression.
• Aged MuSCs, especially in males, showed early alterations like increased inflammation and loss of cell identity.
• Late-stage aging revealed heightened inflammation, enhancer activation, 3D genome rewiring, and links to retroviral expression and NFκB activity.

Conclusions:

• Progressive molecular shifts, including inflammation and epigenetic/genome alterations, occur in MuSCs during aging.
• These age-related changes in MuSCs contribute to impaired proliferation and function, explaining reduced skeletal muscle regeneration.
• The findings highlight key molecular pathways involved in stem cell aging and loss of regenerative potential.