Abstract
The regeneration of the muscle tissue relies on the capacity of the satellite stem cell (SC) population to exit quiescence, divide asymmetrically, proliferate, and differentiate. In age-related muscle atrophy (sarcopenia) and several dystrophies, regeneration cannot compensate for the loss of muscle tissue. These disorders are associated with the depletion of the satellite cell pool or with the loss of satellite cell functionality. Recently, the establishment and maintenance of quiescence in satellite cells have been linked to their metabolic state. In this work, we aimed to modulate metabolism in order to preserve the satellite cell pool. We made use of metformin, a calorie restriction mimicking drug, to ask whether metformin has an effect on quiescence, proliferation, and differentiation of satellite cells. We report that satellite cells, when treated with metformin in vitro, ex vivo, or in vivo, delay activation, Pax7 downregulation, and terminal myogenic differentiation. We correlate the metformin-induced delay in satellite cell activation with the inhibition of the ribosome protein RPS6, one of the downstream effectors of the mTOR pathway. Moreover, in vivo administration of metformin induces a belated regeneration of cardiotoxin- (CTX-) damaged skeletal muscle. Interestingly, satellite cells treated with metformin immediately after isolation are smaller in size and exhibit reduced pyronin Y levels, which suggests that metformin-treated satellite cells are transcriptionally less active. Thus, our study suggests that metformin delays satellite cell activation and differentiation by favoring a quiescent, low metabolic state.
Highlights
Skeletal muscle regeneration relies on the dynamic interplay between satellite cells (SCs) and their environment, the stem cell niche [1]
In order to further investigate the role of metabolic reprogramming in skeletal muscle stem cell fate, here we examine the effect of metformin on SC activation and differentiation in vivo and ex vivo
The percentage of SCs that remains positive for both Pax7 and MyoD is significantly higher after 4 days of metformin treatment when compared to the control, while the fraction of SCs committed to myogenic differentiation (Pax7-/MyoD+) remains significantly lower in the treated sample
Summary
Skeletal muscle regeneration relies on the dynamic interplay between satellite cells (SCs) and their environment, the stem cell niche [1]. Under resting conditions, SCs are mitotically quiescent [2]. Following damage, they are activated and divide asymmetrically. As in Duchenne muscular dystrophy (DMD), chronic inflammation stimulates SC proliferation and differentiation by sending sustained regeneration signals. This phenomenon contributes to the exhaustion of the SC pool and the ensuing decrease in the regeneration potential [5]
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