Impaired regeneration of skeletal muscle in obese individuals is accompanied with fatty degeneration. Retinoic acid (RA) supplementation promotes myogenesis but inhibits white adipogenesis. The objective of this study was to examine the effects of RA on the restoration of skeletal muscle after injury under obese condition and its effects on the physiological functions of fibro/adipogenic progenitors (FAPs) which coordinate regeneration process. ROSA26-RARαDN mice were crossed with Pdgfra-cre/ER mice; in these cross-bred mice (RARαDN), tamoxifen induces RA signaling blockage specific in PDGFRα+ FAPs. Following injury, RA enhanced muscle regeneration, which was abolished due to the blockage of RA signaling in FAPs, accompanied with ectopic adipocyte accumulation, showing the mediatory roles of RA receptor signaling. Consistently, in diet-induced obese mice, muscle regeneration was inhibited but adipogenesis was enhanced; RA effectively reduced adipogenesis in the regenerated skeletal muscle of obese mice, but such beneficial effect disappeared in HFD mice with RA signaling blockage in FAPs.
In summary, our studies showed that RA signaling controls the adipogenic differentiation of FAPs and RA treatment effectively inhibits adipogenesis during skeletal muscle regeneration and promotes muscle repair of obese mice.
L. Zhao: None. M. Zhu: None. M. Du: None.
National Institutes of Health (R01HD067449)