INTER-REGULATION OF CIRCADIAN AND AUTOPHAGIC PROCESSES IN STEM CELLS: IMPACT ON TISSUE REGENERATION AND AGING

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Regeneration of skeletal muscle relies on its stem cells, also called satellite cells (SCs). These cells remain quiescent throughout their life, and only activate in response to injury to form new muscle fibers. The regenerative capacity of these cells declines with aging. In the past years, Pura Muñoz Cánoves’ lab showed that, with aging, quiescent SCs 1) lose basal autophagy and 2) reprogram their circadian transcriptome (including the autophagic transcriptome). The molecular bases of these processes, their potential interrelation and the consequences of their failure with aging, are unknown. Our integrating hypothesis is that active autophagy and circadian regulation are interconnected and required to preserve stem cell regenerative fitness throughout life. We aim to answer the following questions: Which is the relative contribution of the stem-cell-intrinsic versus the organismal clock to muscle regeneration during aging? Are circadian and autophagy processes interconnected? This is, does circadian clock disruption alter autophagy in SCs? Conversely, does autophagy disruption affect their circadian regulation? If so, does autophagy re-induction by nutritional regimes restore circadian and regenerative functions in aged SCs? Mice genetically-modified for depletion of 1) selected circadian clocks or 2) autophagy will allow us to assess the relative contribution and interrelation of autophagic and circadian machineries to muscle regeneration during aging. We expect that completion of this project will provide new fundamental knowledge on stem cell biology, regeneration and aging, which will open opportunities for stem cell rejuvenation.