Cicciarello, D. | Search bioRxiv

bioRxiv2025

The AMPKa2/PHF2 axis is critical for turning over lipid droplets during muscle stem cell fate

Lipid metabolism is a key process required for muscle stem cell (MuSCs) function during regenerative myogenesis. However, the molecular pathway responsible of such regulation is still unknown. Studies of lysine demethylase PHF2 have reported its critical role in lipid metabolism in pathological processes, although there are no data regarding its role during MuSC fate transition. Here we show that PHF2 controls lipid droplet homeostasis in MuSCs during regenerative myogenesis, by promoting the contact between lipid droplets and mitochondria. Consistently, in absence of PHF2, myocytes accumulate lipid droplets, leading to mitochondrial dysfunction and impaired regeneration. Interestingly, such phenotype is rescued by AMPK2-PHF2 phospho-mimetic mutant expression. Our findings provide evidence that PHF2 is part of AMPK2 signaling and underscore the critical role of AMPK2/PHF2 axis in regulating lipid droplets homeostasis during MuSC fate.

cell biology↗

bioRxiv2022

LSD1-mediated demethylation of β-catenin regulates muscle stem cell self-renewal potential.

The Wnt/{beta}-Catenin pathway plays a key role in cell fate determination during development and in adult tissue regeneration by stem cells. These processes involve profound gene expression and epigenome remodeling and linking Wnt/{beta}-Catenin signaling to chromatin modifications has been a challenge over the past decades. Functional studies of the histone demethylase LSD1/KDM1A converge to indicate that this epigenetic regulator is a key regulator of cell fate, although the extracellular cues controlling LSD1 action remain largely unknown. Here we show that {beta}-Catenin is a substrate of LSD1. Demethylation by LSD1 prevents {beta}-Catenin degradation thereby maintaining its nuclear levels. Consistently, in absence of LSD1, {beta}-Catenin transcriptional activity is reduced in both MuSCs and ESCs. Moreover, inactivation of LSD1 in mouse muscle stem cells and embryonic stem cells shows that LSD1 promotes mitotic spindle orientation via {beta}-Catenin protein stabilization. Altogether, by inscribing LSD1 and {beta}-Catenin in the same molecular cascade linking extracellular factors to gene expression, our results provide a mechanistic explanation to the similarity of action of canonical Wnt/{beta}-Catenin signaling and LSD1 on stem cell fate.

developmental biology↗