Retinoic acid signalling in fibro/adipogenic progenitors robustly enhances muscle regeneration

Abstract

Background During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored. Methods Here, we investigated the role of retinoic acid (RA) signalling in regulating FAPs and the subsequent effects on muscle restoration from a cardiotoxin-induced injury. Blockage of retinoic acid receptor (RAR) signalling was achieved through dominant negative retinoic acid receptor α (RARα403) expression specific in PDGFRα+ FAPs in vivo and by BMS493 treatment in vitro . Effects of RAR-signalling on FAP cellularity and muscle regeneration were also investigated in a high-fat diet-induced obese mice model. Findings Supplementation of RA increased the proliferation of FAPs during the early stages of regeneration while suppressing FAP differentiation and promoting apoptosis during the remodelling stage. Loss of RAR-signalling caused ectopic adipogenic differentiation of FAPs and impaired muscle regeneration. Furthermore, obesity disrupted the cellular transition of FAPs and attenuated muscle regeneration. Supplementation of RA to obese mice not only rescued impaired muscle fibre regeneration, but also inhibited infiltration of fat and fibrotic tissues during muscle repair. These beneficial effects were abolished after blocking RAR-signalling in FAPs of obese mice. Interpretation These data suggest that RAR-signalling in FAPs is a critical therapeutic target for suppressing differentiation of FAPs and facilitating the regeneration of muscle and other tissues. Funding This study was supported by grants from the National Institutes of Health (R01-HD067449 and R21-AG049976) to M.D.

Fibro-adipogenic progenitors in skeletal muscle homeostasis, regeneration and diseases

“…Consistently, deletion of FAPs cilia over-activates Hedgehog signalling and prevents adipogenesis following glycerol-induced muscle injury [ 36 ]. Another study indicated that retinoic acid receptor signalling plays an important role in the intrinsic regulation of FAPs number and cell fate decision [ 57 ]. Treatment of FAPs with retinoic acid promotes their proliferation in vitro and inhibits their adipogenic and fibrogenic differentiation both in vitro and in vivo (in obese mice fed with high-fat diet) [ 57 ].…”

Signaling pathways regulating the fate of fibro/adipogenic progenitors (FAPs) in skeletal muscle regeneration and disease

“…Recently, this signaling was also explored also in the regeneration context focusing on FAP biology. Here, RA improves muscle regeneration upon acute injury and successfully limits FAP differentiation into adipocytes both in vitro and in vivo [69]. Specifically, exogenous addition of RA to FAP cultures halts their adipogenic differentiation [69] and pharmacological inhibition of RAR receptors reverts such inhibitory effect.…”

“…Specifically, exogenous addition of RA to FAP cultures halts their adipogenic differentiation [69] and pharmacological inhibition of RAR receptors reverts such inhibitory effect. Supplementation of RA stimulates FAP proliferation while facilitating FAP apoptosis during the remodeling stage [69]. Expression of conditional dominant negative Retinoic acid receptor alpha (RAR-alpha 403 ) in FAPs causes ectopic adipogenesis and impairs muscle regeneration [69].…”

“…Supplementation of RA stimulates FAP proliferation while facilitating FAP apoptosis during the remodeling stage [69]. Expression of conditional dominant negative Retinoic acid receptor alpha (RAR-alpha 403 ) in FAPs causes ectopic adipogenesis and impairs muscle regeneration [69]. Supplementation of RA to obese mice improves muscle fiber regeneration and inhibits infiltration of fat and fibrotic tissues during muscle repair [69].…”

“…Expression of conditional dominant negative Retinoic acid receptor alpha (RAR-alpha 403 ) in FAPs causes ectopic adipogenesis and impairs muscle regeneration [69]. Supplementation of RA to obese mice improves muscle fiber regeneration and inhibits infiltration of fat and fibrotic tissues during muscle repair [69]. These beneficial effects are abolished after blocking RAR-signaling in FAPs of obese mice [69].…”