Long-term DNA methylation changes induced by age and elevated CO₂ in skeletal muscle

Area of Science:

• Epigenetics
• Skeletal Muscle Physiology
• Pulmonary Disease Research

Background:

• Skeletal muscle dysfunction and hypercapnia (elevated CO2) are linked to mortality in pulmonary diseases.
• Aging, hypercapnia, and autophagy dysfunction share overlapping skeletal muscle phenotypes.
• Previous studies on DNA methylation in skeletal muscle are limited in scope; whole-genome comparisons of CO2- and age-induced changes are lacking.

Purpose of the Study:

• To comparatively analyze whole-genome DNA methylation and gene expression changes in skeletal muscle induced by hypercapnia versus aging.
• To investigate the persistence of hypercapnia-induced skeletal muscle alterations.
• To explore the underlying mechanisms, including autophagy and substrate balance, in hypercapnia-induced epigenetic modifications.

Main Methods:

• Whole genome methylation sequencing (WGMS) and RNA sequencing were performed on mice exposed to normo- and hypercapnia, and aged mice.
• Comparative analysis of DNA methylation and transcript expression overlap between hypercapnia and aging.
• Skeletal muscle-specific autophagy genetic ablation and mass spectrometry were used to investigate mechanisms.

Main Results:

• Hypercapnia induced aberrant DNA methylation patterns and myofiber type changes in skeletal muscle.
• Muscle mass deterioration persisted even after returning to normocapnia.
• CO2-induced DNA methylation changes did not overlap with age-related epigenetic changes.
• Hypercapnia did not affect the methylome via autophagy or substrate imbalance.

Conclusions:

• Hypercapnia induces persistent skeletal muscle wasting associated with a disrupted methylome.
• CO2-induced epigenetic alterations are distinct from age-related changes and are independent of autophagy and substrate regulation.