Aging disrupts gene expression timing during muscle regeneration

Area of Science:

• Muscle biology
• Aging research
• Molecular genetics

Background:

• Skeletal muscle function and regeneration decline with age.
• The precise molecular mechanisms driving age-related muscle decline are not fully understood.
• Muscle regeneration involves complex, coordinated transcriptional programs in myogenic stem cells.

Purpose of the Study:

• To investigate global changes in myogenic transcriptional programs during muscle regeneration in aged versus young mice.
• To identify age-specific differences in the coordination of gene expression critical for muscle repair.
• To understand how disruptions in these programs contribute to compromised regeneration in aging.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was performed on myogenic nuclei from injured muscles of aged and young mice.
• Pseudotime trajectories were analyzed to model the temporal progression of myogenic transcription programs.
• Dynamic time warping was employed to compare and quantify differences in pseudotemporal alignment between aged and young groups.

Main Results:

• Significant age-specific differences were observed in the coordination of myogenic transcription programs following muscle injury.
• Pseudotemporal differences between aged and young mice became progressively more pronounced as regeneration advanced.
• Disruptions in the timing of key myogenic gene expression programs were identified in aged muscle regeneration.

Conclusions:

• Aging alters the temporal coordination of transcriptional programs essential for skeletal muscle regeneration.
• These disruptions in gene expression timing likely contribute to incomplete muscle repair and functional decline in aged individuals.
• Understanding these age-related molecular timing deficits is crucial for developing strategies to improve muscle regeneration in the elderly.