Vitamin A retinoic acid contributes to muscle stem cell and mitochondrial function loss in old age
Paula M. Fraczek, … , Jacqueline A. Larouche, Carlos A. Aguilar
Paula M. Fraczek, … , Jacqueline A. Larouche, Carlos A. Aguilar
Published March 25, 2025
Citation Information: JCI Insight. 2025;10(9):e183706. https://doi.org/10.1172/jci.insight.183706.
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Research Article Aging Muscle biology Stem cells

Vitamin A retinoic acid contributes to muscle stem cell and mitochondrial function loss in old age

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 a 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 that 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.

Authors

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

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Figure 5

The vitamin A receptor Stra6 is attenuated with stem cell activation and aging.

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The vitamin A receptor Stra6 is attenuated with stem cell activation and...
(A) Schematic depicting how Stra6 expression decreases with muscle stem cell activation and differentiation. (B) Quantification of Stra6 expression fold change (relative to Gapdh) in freshly isolated MuSCs, activated myoblasts (72 hours in culture with growth medium), and differentiated myotubes (an additional 72 hours in culture with differentiation medium). qPCR was run using 2 biological replicates and 2 technical replicates per time point. (C) Representative immunofluorescence images of Stra6 from muscle stem cells isolated from freshly isolated young (3–4 months) and aged mice (22 months). Tissues from 2 biological replicates (C57BL/6 females) were used per age group and pooled during MACS isolation before seeding into a 96-well plate, fixing, and labeling for Stra6. (D) Quantification of Stra6 mean fluorescence intensity comparing age groups using a t test. n = 8 wells were imaged per age group. (E) Representative images of Stra6 immunofluorescence staining in old-aged MuSCs (pooled from n = two 24-month-old female C57BL/6 mice) treated with DMSO vehicle control (top) or agonists and ATRA (bottom) for 3 days. Stra6, green; DAPI, blue. Scale bar: 50 μm. (F) Quantification of Stra6 mean fluorescence intensity between old-aged MuSCs treated with DMSO vehicle control (blue) or agonists and ATRA (red). Comparison made via t test with n = 4 wells per treatment. (G) Representative images of MyoD immunofluorescence staining in old-aged MuSCs treated with DMSO vehicle control (top) or agonists and ATRA (bottom). MyoD, yellow; DAPI, blue. Scale bar: 50 μm. (H) Quantification of MyoD mean fluorescence intensity between aged MuSCs treated with DMSO vehicle control or agonists and ATRA. Comparison made via t test with n = 4 wells per treatment.