Large Maf Transcription Factors Reawaken Evolutionarily Dormant Fast-Glycolytic Type IIb Myofibers in Human Skeletal Muscle

Small mammals, such as mice, rely on the rapid contraction of skeletal muscles to achieve swift movements. These capabilities are enabled by type IIb myofibers, which express the fastest myosin IIb in limb muscles, encoded by MYH4. In contrast, larger mammals, including humans, exhibit a marked reduction or complete absence of type IIb myofibers and MYH4 expression, favoring slower-contracting myofiber types. The evolutionary shift away from MYH4 expression in larger mammals and the underlying regulatory mechanisms remain poorly understood. Previously, we identified the large Maf transcription factor family (Mafa, Mafb, Maf) as principal regulators of type IIb myofiber determination in mice. Here, we provide the first evidence that the large MAFs specifically induces MYH4 expression in the skeletal muscles of large mammals, including humans and bovine. Furthermore, induction of MYH4 by large MAFs significantly enhances the glycolytic capacity of human myotubes, as evidenced by flux analyzer data and RNA-seq showing the upregulation of numerous genes associated with glucose metabolism. Lastly, RNA-seq analysis of human muscle biopsies reveals a positive correlation between MAFA, MAF, and MYH4 expression. Our findings propose that the large MAFs promotes the formation of the fastest type IIb myofibers in the skeletal muscles of large mammals. This discovery not only elucidates the mechanisms underlying the loss of type IIb myofibers in larger mammals but also holds potential implications for enhancing athletic performance and counteracting the loss of fast-twitch myofibers associated with aging.