Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Abstract Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy and aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screening of 1120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). To our surprise we found the hit list enriched for the glucocorticoid chemical class (GCs). Glucorticoids are often described as drugs that promote adipogenesis in vitro and in vivo. To shed light on conflicting reports we further characterized by different approaches three GCs identified in our screening focusing on budesonide a potent inhibitor of adipogenesis. We found that, similarly to dexamethasone, budesonide inhibits adipogenesis induced by insulin on subconfuent FAPs. However, both drugs have a proadipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. By gene expression analysis we observed that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Finally, we noticed that alongside their anti-adipogenic effect, GCs promote terminal differentiation of satellite cells. Both the pro-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor as they are not observed in the presence of receptor inhibitor. Steroid administration currently represents the standard treatment of DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.