The Effects of Exercise on LINE-1 Regulation

Abstract

Transposable elements (TEs) are mobile DNA and constitute approximately half of the human genome. LINE-1 (L1) is the only active autonomous TE in the mammalian genome and has been implicated, either directly or indirectly, in a number of diseases as well as aging. We have previously reported that L1 expression is lower in skeletal muscle after both acute and chronic resistance training in college-aged males. Building on these findings, we used a rodent model of exercise to better dissect the effects of exercise on skeletal muscle L1 regulation. Intrinsically high running female Wistar rats (n=11 per group) were either given access to a running wheel (EX) or not (SED) at 5 weeks of age, and these conditions were maintained until the rats reached 27 weeks of age. Thereafter mixed gastrocnemius tissue was harvested and analyzed for L1 mRNA expression and DNA content along with other markers involved with L1 regulation. We observed significantly (p<0.05) lower L1 mRNA expression, higher L1 DNA methylation, and less L1 DNA in accessible chromatin regions in EX versus SED rats. We followed these experiments with in vitro drug treatments in L6 myotubes, which served to mimic exercise-specific signaling events. We found that 4mM 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which increases AMPK signaling, decreased L1 mRNA expression in L6 myotubes. Our results suggest that long-term voluntary wheel running has the ability to downregulate L1 mRNA via increased DNA methylation and chromatin changes, and these phenomena may be mediated through AMPK signaling.