Gli1 regulates fibro/adipogenic progenitor function through modulation of Ido1 in muscle regeneration

TL;DR

This study shows that Gli1 helps muscle repair by controlling the behavior of fibro/adipogenic progenitors through Ido1, a key enzyme in metabolism.

Contribution

The study reveals a novel role for Gli1 in muscle regeneration by modulating FAP function through Ido1.

Findings

Gli1 is primarily expressed in MuSCs and FAPs in skeletal muscle.

Loss of Gli1 in FAPs impairs muscle regeneration and increases adipogenic potential.

Gli1 activates Ido1 transcription, and Ido1 inhibition mimics the effects of Gli1 loss.

Abstract

Gli1 is a critical marker of diverse stem cell populations across multiple tissues and is essential for tissue regeneration. However, its functional relevance in skeletal muscle has remained largely unexplored. Here, we demonstrate that Gli1 primarily expressed in muscle stem cells (MuSCs) and fibro/adipogenic progenitors (FAPs) in skeletal muscle. Utilizing conditional knockout mouse models, we found that systemic loss of Gli1 impairs muscle regeneration; however, this effect is not attributable to MuSC-dependent mechanisms. Rather, conditional deletion of Gli1 in FAPs lead to significant regenerative impairment, characterized by aberrant FAP expansion and their enhanced adipogenic potential. In vivo, Gli1-deficient FAPs contributed to increased intramuscular adipocyte accumulation, while in vitro assays confirmed enhanced lipid droplet formation under adipogenic conditions. Mechanistically, Gli1 directly activates the transcription of the key metabolic enzyme indoleamine 2,3-dioxygenase 1 (Ido1), and inhibition or knockdown of Ido1 phenocopied the effects of Gli1 loss. Together, these findings uncover a previously unrecognized role for Gli1 in orchestrating muscle regeneration by modulating FAP fate and function, providing new insights into the cellular and molecular framework governing muscle repair.

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