Hypercapnia induces long-term DNA methylation changes in skeletal muscle.
Skeletal muscle dysfunction and elevated CO2 in the blood, or hypercapnia, are both associated with higher mortality in acute and chronic pulmonary diseases. Hypercapnia causes accelerated protein degradation, reduced protein synthesis, and dysfunctional myogenesis. We have recently reported that hypercapnia-induced skeletal myogenic dysfunction persists after resolution of CO2 exposure, suggesting the existence of durable cellular aberrations in previously hypercapnic cells. No data on lingering myofiber atrophy after hypercapnia resolution currently exist. Hypercapnia and age-induced skeletal muscle loss phenotypically overlap, and myogenic progenitor cells from hypercapnic mice elicit senescence-associated transcriptional programs. While aging is characterized by unique DNA methylation and other epigenetic changes, the potential association of hypercapnia and age-related differential methylation have never been investigated. In the present study, we show that hypercapnic mice elicit protracted muscle deterioration even after returning to normocapnia and demonstrate aberrant DNA methylation in comparison to animals never exposed to elevated CO2. We also show that these DNA methylation changes do not overlap with age-induced alterations. Overall design: RNA sequencing of skeletal muscle tissue from mice exposed to hypercapnic conditions, six months post-hypercapnia, and mice through three aging stages