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Resource and Technical AdvanceIn-Press PreviewAgingMuscle biologyStem cells Open Access | 10.1172/jci.insight.183706

Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age

Paula M. Fraczek,1 Pamela Duran,1 Benjamin A. Yang,1 Valeria Ferre,1 Leanne Alawieh,1 Jesus A. Castor-Macias,1 Vivian T. Wong,1 Steve D. Guzman,1 Celeste Piotto,1 Klimentini Itsani,1 Jacqueline A Larouche,1 and Carlos A. Aguilar1

1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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1Deptartment of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America

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Published March 25, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.183706.
Copyright © 2025, Fraczek et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 25, 2025 - Version history
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Abstract

Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.

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  • Version 1 (March 25, 2025): In-Press Preview
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