Fat1 deletion enhances Fibro-Adipogenic Differentiation and Adipogenic expansion following injury in skeletal muscle

Skeletal muscles regenerate following injury, owing not only to myogenic stem cells, but also to non-myogenic cells such as fibro-adipogenic progenitors (FAPs). Quiescent in healthy muscles, FAPs transiently proliferate in response to tissue-damage, to support myogenic repair. Aside from their pro-myogenic role in healthy muscles, FAPs are also the origin of intramuscular fibro-adipose tissue that infiltrate muscles with chronic inflammation and degeneration in various muscle pathologies. Here, we investigate how the Fat1 Cadherin, previously identified as a regulator of embryonic muscle morphogenesis, influences FAP biology during damage-induced muscle regeneration. Fat1 expression is transiently induced in FAPs and myogenic cells after muscle damage. We found that mesenchyme-specific Fat1 ablation leads to increased fibro-adipogenic infiltrations following glycerol injury, while minimally affecting myogenic repair. Using an inducible Pdgfra-cre/ERT line, we further demonstrated that Fat1 restricts FAP adipogenic differentiation through both cell-autonomous and non-cell-autonomous mechanisms. These findings identify Fat1 as a novel regulator of FAP biology, essential for limiting FAP differentiation and the development of fibro-fatty infiltrations after muscle injury.