Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling (Zfp697 skeletal muscle knockout RNA-Seq of unloading-reloading protocol)

Muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and ageing. Recovery from atrophy involves changes in protein synthesis and different cell types such as muscle fibers, and satellite and immune cells. Here we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle regeneration. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Myofiber-specific Zfp697 ablation hinders the inflammatory and regenerative response to muscle injury, compromising functional recovery. We uncover Zfp697 as an essential mediator of the interferon gamma response in muscle cells that functions primarily as an ncRNA-binding protein, most notably the pro-regenerative miR-206. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue regeneration.