49. LOSS OF HYPOXIA SIGNALING LIMITS PHYSIOLOGIC AND MUSCLE ADAPTATIONS TO AEROBIC EXERCISE IN AGING

Abstract

PURPOSE: This study investigates signaling pathways which contribute to aging associated loss of muscle adaptation to exercise. METHODS: Young (Y, 12 weeks) and Old (O, 25 months) mice were subjected to regimented treadmill running or no exercise for 8 weeks. Mice were then subjected to muscle physiology testing. The transcriptional response to exercise was evaluated using RNA Seq. A genetically modified mouse model, with a deletion of aryl hydrocarbon receptor nuclear translocator (ARNT) was then evaluated for response to exercise training as it mimics old mice with regards to transcription profile and exercise response. RESULTS: Y, trained mice experienced a significant increase in distance running, speed, and lean muscle mass in comparison to untrained controls. O mice did not improve significantly in these measures. Transcriptome analysis in muscle from Y mice demonstrated differential regulation of 96 genes with exercise. None of these genes were similarly regulated in the O group. Genes most upregulated in Y mice are targets of hypoxia signaling. ARNT, a regulator of hypoxia signaling, increased 3-fold with exercise in Y mice, but not in O mice following exercise. To assess whether loss of ARNT impairs the exercise response, we generated a mouse with muscle-specific knockout of ARNT (ARNT muscle (mKO). Following regimented exercise, ARNT mKO mice did not improve maximal distance running, maximal running speed, or lean muscle mass. Administration of an ARNT agonist restored the exercise response. CONCLUSION: Restoration of ARNT and hypoxia signaling may restore the physiologic response to exercise in aging.