Bachelor of Science, Yonsei University (2012)
Doctor of Philosophy, Seoul National University (2019)
Master of Science, Yonsei University (2014)
Thomas Rando, Postdoctoral Faculty Sponsor
Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling.
Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here, we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet or exogenously administered, promotes a deep quiescent state in muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Furthermore, we show that ketone bodies, specifically beta-hydroxybutyrate, directly promote MuSC deep quiescence via a nonmetabolic mechanism. We show that beta-hydroxybutyrate functions as an HDAC inhibitor within MuSCs, leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
View details for DOI 10.1016/j.cmet.2022.04.012
View details for PubMedID 35584694
ATR activity controls stem cell quiescence via the cyclin F-SCF complex.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (18): e2115638119
SignificanceThe replication stress response protein, ATR, is active in quiescent muscle stem cells in response to DNA:RNA hybrids, and this activity maintains quiescence by ensuring degradation of key cell-cycle transition factors by the E3 ubiquitin ligase cyclin F-SCF complex. This is critical for understanding how stem cells regulate a state of prolonged and reversible cell-cycle arrest and how genome integrity is maintained over time. Together, these studies offer a unique picture of a molecular mechanism controlling stem cell quiescence.
View details for DOI 10.1073/pnas.2115638119
View details for PubMedID 35476521