Abstract IA18: Clock Control of HIF Activity and Muscle Tissue Regeneration

Circadian clocks generate rhythmic pulses of glucose metabolism and respiration to divide energy-producing and energy-consuming processes into separate periods in the light-dark cycle. At the cellular level, clocks direct the expression of thousands of genes involved in metabolism, tissue growth, and repair, yet our understanding of how clocks detect signals in the environment to coordinate transcription and metabolic flux at precise stages during development and in post-mitotic cells remains poorly understood. A breakthrough in understanding circadian mechanisms in metabolic plasticity came from our discovery that molecular clock transcription factors respond to changes in environmental oxygen. We uncovered a link between circadian clocks and the control of the oxygen- and mitochondrial stress-responsive hypoxia-inducible factor (HIF) pathway, which controls adaptation to low oxygen environments, such as during tumorigenesis and ischemic injury. Here, we demonstrate a role for the circadian clock in post-muscle injury myogenesis and tissue regeneration. Indeed, loss of Bmal1 in adult muscle stem cell populations leads to impaired regeneration after ischemic muscle injury in mice. Furthermore, we observe time-of-day differences in muscle regeneration rates, with more rapid tissue repair following injury during the dark (active) phase. In addition, myogenesis is reduced in primary Bmal1-/- myoblasts compared to controls, a phenotype that is exaggerated in hypoxic conditions. Finally, we observe that loss of Bmal1 in myoblasts leads to chromatin remodeling that alters transcription of genes involved in metabolic flux and myogenic gene expression. Together, our studies demonstrate that circadian clocks in muscle stem cells control metabolic and genomic reprogramming under hypoxia to regulate in vitro myogenesis and in vivo skeletal muscle regeneration. Citation Format: Clara Bien Peek. Clock Control of HIF Activity and Muscle Tissue Regeneration [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA18.