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  • Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling. Cell metabolism Benjamin, D. I., Both, P., Benjamin, J. S., Nutter, C. W., Tan, J. H., Kang, J., Machado, L. A., Klein, J. D., de Morree, A., Kim, S., Liu, L., Dulay, H., Feraboli, L., Louie, S. M., Nomura, D. K., Rando, T. A. 2022

    Abstract

    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

  • Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1 NATURE METABOLISM Brett, J. O., Arjona, M., Ikeda, M., Quarta, M., de Morree, A., Egner, I. M., Perandini, L. A., Ishak, H. D., Goshayeshi, A., Benjamin, D. I., Both, P., Rodriguez-Mateo, C., Betley, M. J., Wyss-Coray, T., Rando, T. A. 2020; 2 (4): 307-+

    View details for DOI 10.1038/s42255-020-0190-0

    View details for Web of Science ID 000536044100005

  • Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1. Nature metabolism Brett, J. O., Arjona, M., Ikeda, M., Quarta, M., de Morrée, A., Egner, I. M., Perandini, L. A., Ishak, H. D., Goshayeshi, A., Benjamin, D. I., Both, P., Rodríguez-Mateo, C., Betley, M. J., Wyss-Coray, T., Rando, T. A. 2020; 2 (4): 307-317

    Abstract

    Aging impairs tissue repair. This is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young adult animals but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis. One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem cell function in the context of tissue regeneration are incompletely understood. Here we show that exercise in the form of voluntary wheel running accelerates muscle repair in old animals and improves old MuSC function. Through transcriptional profiling and genetic studies, we discovered that the restoration of old MuSC activation ability hinges on restoration of Cyclin D1, whose expression declines with age in MuSCs. Pharmacologic studies revealed that Cyclin D1 maintains MuSC activation capacity by repressing TGFβ signaling. Taken together, these studies demonstrate that voluntary exercise is a practicable intervention for old MuSC rejuvenation. Furthermore, this work highlights the distinct role of Cyclin D1 in stem cell quiescence.

    View details for DOI 10.1038/s42255-020-0190-0

    View details for PubMedID 32601609

    View details for PubMedCentralID PMC7323974