Large Maf transcription factor family is a major regulator of fast type IIb myofiber determination.

Myofibers are broadly characterized as fatigue-resistant slow-twitch (type I) fibers and rapidly fatiguing fast-twitch (type IIa/IIx/IIb) fibers. However, the molecular regulation of myofiber type is not entirely understood; particularly, information on regulators of fast-twitch muscle is scarce. Here, we demonstrate that the large Maf transcription factor family dictates fast type IIb myofiber specification in mice. Remarkably, the ablation of three large Mafs leads to the drastic loss of type IIb myofibers, resulting in enhanced endurance capacity and the reduction of muscle force. Conversely, the overexpression of each large Maf in the type I soleus muscle induces type IIb myofibers. Mechanistically, a large Maf directly binds to the Maf recognition element on the promoter of myosin heavy chain 4 , which encodes the type IIb myosin heavy chain, driving its expression. This work identifies the large Maf transcription factor family as a major regulator for fast type IIb muscle determination. [Display omitted] • Large Mafs are predominantly expressed in fast-twitch skeletal muscles • Large Maf ablation in skeletal muscle depletes fast type IIb myofiber content • Large Mafs specifically bind to the Maf recognition elements of the Myh4 promoter • Overexpression of a large Maf induces fast type IIb myofibers in adult soleus muscle Sadaki et al. identify large Mafs as major regulators of type IIb myofiber specification. Large Maf-deficient skeletal muscles show severe loss of type IIb myofibers, with a myofiber type shift toward IIx/IIa. Conversely, single large Maf overexpression enhances type IIb myofiber formation through Maf recognition elements in the Myh4 promoter. [ABSTRACT FROM AUTHOR]