MAFF is a transcription factor that regulates contraction-induced skeletal muscle transcription.

Skeletal muscle adapts to exercise through rapid transcriptional remodeling, but regulators that link contractile activity to these gene programs remain unclear. Here we show that MAFF, a small MAF transcription factor, is consistently induced by acute exercise in both human and mouse skeletal muscle, with induction restricted to muscles recruited by the exercise modality. In C2C12 cells, Maff was induced by in vitro electrical pulse stimulation model. Using CRISPR/Cas9-mediated Maff knockout C2C12 cells, we found that loss of Maff reduced myogenic fusion with accumulation of unfused nuclei. RNA sequencing revealed broad reprogramming in Maff-deficient myotubes, including reduced expression of muscle structural and contractile genes and increased interferon/immune responses and extracellular matrix-related signatures. Moreover, Maff deficiency attenuated a subset of electrical pulse stimulation-responsive genes. Together, these data identify MAFF as a component of the transcriptional machinery supporting myogenic maturation and contraction-evoked gene regulation.