Objective

Communication between Muscle Stem Cells (MuSC) and its microenvironment is crucial for MuSC homeostasis and ensure proper regenerative capacity. Consequent alterations of the microenvironment that occur during aging lead to functional loss and exhaustion of the MuSC pool. This has been related, at least partially, to the Wnt-β-catenin increased signaling in aged individuals.

Previously, we showed that the lysine demethylase LSD1, regulating β-catenin stability, fine tunes the MuSC response to the Wnt signaling.

Therefore, we hypothesized that inhibiting LSD1 could be a relevant strategy to face Wnt-related impairment during skeletal muscle regeneration.

Methods

12 months old mice, specifically depleted of LSD1 in MuSCs after 5 days of tamoxifen injection, were used. Myogenic potential of MuSCs were tested in vitro, ex vivo and in vivo upon cardiotoxin injury.

Results

Here we show that depletion of LSD1 does not affect aged MuSCs homeostasis in 12 months old mice. Interestingly, 28 days after cardiotoxin injection, LSD1 Knock out (KO) mouse muscles display a significant increase of self-renewed MuSCs. Despite an equal number of fibers, we observed a significant increase of bigger fibers in LSD1 KO muscles compared to controls suggesting a better regeneration potential in absence of LSD1. However, in vitro experiments do not recapitulate such phenotype. Indeed, LSD1 KO aged MuSCs commitment and fusion capacity is significantly impaired compared to control MuSCs.

Conclusion

Our results demonstrate that intrinsic LSD1-depleted aged MuSC regenerative capacities are impaired. However, the difference between in vivo and in vitro experiments highlights the importance of the crosstalk between MuSCs and the microenvironment, supporting the hypothesis that LSD1 acts as a sensor of the microenvironment.