Vitamin A-Derived Retinoic Acid Contributes to Muscle Stem Cell and Mitochondrial Function [scRNA-Seq]

Vitamin A is an exogenous micronutrient that is derived solely from diet and metabolized into retinoic acid, which acts as an antioxidant and transcriptional regulator. Here we show that obstruction of dietary Vitamin A drives mitochondrial and cell cycle dysfunction in MuSCs and myoblasts that mimics old age. The receptor for vitamin A derived retinol, Stra6, was found to be diminished with MuSC activation and in old age. The loss of Stra6 in myogenic progenitors resulted in accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. Pharmacological targeting of Stra6 and retinoic acid signaling in myogenic progenitors and aged MuSCs reverted oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence. These results demonstrate that Vitamin A regulates mitochondria and metabolism in MuSCs to promote quiescence. These results highlight a unique mechanism connecting stem cell function with vitamin intake. Overall design: Aged (24 months) female C57 Bl/6J mice were administered 3 intramuscular (in the tibialis anterior, gastrocnemius, and quadricep muscles) injections of ATRA, CD3254, and BMS961 or a DMSO vehicle control over the course of a week. After treatment, hindlimb muscles were dissected and digested, and single cell suspensions were submitted for 10x Genomics single cell RNA-sequencing. n=2 mice were pooled per condition for scRNA-Seq.