c-MAF transduces motor neuron firing to sustain fast-glycolytic myofibers and neuromuscular junctions

Jauliac, E.; Backer, S.; Sadaki, S.; GONDIN, J.; Fessard, A.; Escoffier, H.; Roullat, M.; Di Gallo, M.; Levesque, A.; Pereira, D.; Dos Santos, M.; Vuong, V.; Ham, A.; Letourneur, F.; Pierre, R.; Ruegg, M. A.; Birchmeier, C.; Fujita, R.; Sotiropoulos, A.; Maire, P.

doi:10.64898/2026.02.05.703983

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bioRxiv · 10.64898/2026.02.05.703983

c-MAF transduces motor neuron firing to sustain fast-glycolytic myofibers and neuromuscular junctions

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Abstract

This study examined how motoneuron activity influences transcription factor binding in mouse fast glycolytic Myh4+ muscle fibers. Single nucleus multiomics of innervated versus denervated tibialis anterior muscles revealed altered chromatin accessibility: SIX and c-MAF binding sites decreased while JUN, FOS, and RUNX1 sites increased in denervated Myh4+ myonuclei. c-MAF showed strong nuclear enrichment after 100 Hz stimulation and periods of increased motoneuron activity but was absent following denervation, establishing it as a primary readout of fast motoneuron firing. Genome-wide analysis demonstrated that c-MAF binding site spacing encodes functionally distinct muscle gene programs. Analysis of constitutive and inducible skeletal muscle-specific c-Maf mutants revealed that c-MAF loss caused region-specific MYH4+ fiber atrophy, MYH1/MYH2 fiber type shifts resembling ALS G93A mouse phenotypes, and progressive neuromuscular junction fragmentation with increased motoneuron terminal sprouting and ectopic reinnervation. These findings establish c-MAF as a critical mediator linking motoneuron activity to muscle gene regulation, fiber integrity, and neuromuscular junction maintenance in fast glycolytic fibers.

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Jauliac, E., Backer, S., Sadaki, S., GONDIN, J., Fessard, A., Escoffier, H., Roullat, M., Di Gallo, M., Levesque, A., Pereira, D., Dos Santos, M., Vuong, V., Ham, A., Letourneur, F., Pierre, R., Ruegg, M. A., Birchmeier, C., Fujita, R., Sotiropoulos, A., Maire, P.. 2026-02-08. c-MAF transduces motor neuron firing to sustain fast-glycolytic myofibers and neuromuscular junctions. https://doi.org/10.64898/2026.02.05.703983

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