The Age-Dependent Resident Myonuclear Multi-Omic Response to a Skeletal Muscle Hypertrophic Stimulus

Area of Science:

• Muscle physiology
• Molecular biology
• Gerontology

Background:

• Skeletal muscle plasticity is crucial for maintaining function, but it declines with age.
• Myonuclei, the nuclei within muscle fibers, play a key role in regulating muscle adaptation.
• Understanding how myonuclei respond to stimuli in aged muscle is vital for addressing age-related muscle loss.

Purpose of the Study:

• To comprehensively analyze the molecular responses of muscle fiber nuclei (myonuclei) to mechanical overload in adult and aged mice.
• To identify age-dependent differences in myonuclear gene expression and DNA methylation.
• To uncover molecular targets for improving aged muscle adaptability.

Main Methods:

• Utilized doxycycline-inducible myonucleus-specific fluorescent labeling for tracking.
• Performed tissue RNA-sequencing and single myonucleus RNA-sequencing.
• Conducted myonuclear DNA methylation analysis and multi-omic integration.

Main Results:

• Identified conserved microRNA-mediated mechanisms in transcriptional responses to loading across ages.
• Found age-dependent differences in DNA methylation patterns around key hypertrophy genes in myonuclei.
• Observed distinct transcriptomic profiles in adult and aged myonuclei, including innervation and sarcomere assembly-related transcripts.
• Highlighted the role of neuromuscular junction regulation in age-specific muscle hypertrophy.

Conclusions:

• Age-related changes in myonuclear gene expression and DNA methylation impact skeletal muscle's response to mechanical stimuli.
• MicroRNA regulation and DNA methylation are critical in mediating age-dependent muscle plasticity.
• These findings provide a molecular roadmap for interventions to enhance muscle adaptability in aging individuals.