Retinoic acid regulates the activity of satellite cells and promotes skeletal muscle regeneration impaired due to obesity in mice

Background Ectopic lipid accumulation in skeletal muscle induced by obesity leads to muscle atrophy and impaired regenerative capacity. Retinoic acid (RA) has been reported to enhance myogenesis in embryonic stem cells and promotes regeneration in adult skeletal muscle. However, the effects of RA on muscle regeneration impaired due to obesity have not been addressed. The objective of this study is to explore the effects of RA on activation and myogenic differentiation of satellite cells (SCs) in obese mice, which promote muscle regeneration. Methods Transgenic Pax7 cre /ROSA mT/mG mice were used for lineage tracing of SCs. Obesity was induced by feeding 60% high fat diet for 10 weeks. Two days following tamoxifen injection, 10 mg/kg body weight (BDW) RA or equivalent vehicle were injected subcutaneously into the tibialis anterior (TA) muscle of mice once per two days before injury, and TA muscle injury was induced by cardiotoxin injection. The effects of RA supplementation on SCs and corresponding skeletal muscle regeneration were evaluated at different times post‐injury. Results Histological analysis showed that RA supplementation improved muscle fiber regeneration and recovery in obese mice at day 7 post‐injury. The number of SCs in the muscle of obese mice at 3 days post‐injury were increased and the fusion of SCs into regenerated muscle fibers at 7 days post‐injury were promoted in RA treated group. Correspondingly, RA supplementation increased the expression of retinoic acid receptor α (RARα) in the TA muscle samples. The expression of myogenesis genes such as Pax7, Myf5, MyoD and myogenin were increased in muscles with RA treatment. Compared with the vehicle treated group, inflammatory responses including expression of IL6 and TNFα at day 3 and IL1β and IL18 at day 7 were decreased in the skeletal muscle of mice with RA treatment. RA supplementation also increased the expression of insulin like growth factor 1 (IGF1) in muscle at day 3 post‐injury. Conclusions Retinoic acid promoted regeneration and repair of muscle fibers after injury in obese mice accompanied by increased retinoic acid signaling, elevated expression of IGF1 and resolution of inflammation in the regenerating muscle. These benefits could be attributed to enhanced proliferation and myogenic differentiation of SCs after RA treatment. Support or Funding Information Supported by NIH Grant R01HD067449. Effects of retinoic acid (RA) supplementation on skeletal muscle regeneration. H&E staining (A, D) and fluorescence images (B, E) of tibialis anterior (TA) muscle at 3‐ and 7‐days post‐injury (dpi). Green fluorescence tracked Pax7+ satellite cells and derived muscle fibers (regenerated) after tamoxifen induction while red fluorescence showed original cells. C, F. mRNA expression. *p<0.05, ** p<0.01. Data are expressed as mean ±SEM (n=3). image Effects of retinoic acid (RA) supplementation on skeletal muscle regeneration. H&E staining (A, D) and fluorescence images (B, E) of tibialis anterior (TA) muscle at 3‐ and 7‐days post‐injury (dpi). Green fluorescence tracked Pax7+ satellite cells and derived muscle fibers (regenerated) after tamoxifen induction while red fluorescence showed original cells. C, F. mRNA expression. *p<0.05, ** p<0.01. Data are expressed as mean ±SEM (n=3). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .