Wenchao, G. | bioRxiv Science

bioRxiv2024

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

Small mammals rely on type IIb myofibers, expressing the fastest myosin IIb (encoded by MYH4), for rapid muscle contraction. In contrast, larger mammals, including humans, show reduced or absent MYH4 expression and type IIb myofibers, favoring slower-contracting myofibers. The evolutionary mechanisms underlying this shift remain unclear. Here, we identify large MAF transcription factors (MAFA, MAFB, MAF) as key regulators of MYH4 expression in large mammals, including human and bovine. Overexpression of large MAFs induces MYH4 expression and enhances glycolytic capacity in human myotubes, supported by RNA-seq and metabolic flux analyses. RNA-seq of human muscle biopsies reveals a positive correlation between MAFA, MAF, and MYH4 expression, with these genes elevated in power-trained individuals. These findings reveal a conserved mechanism across mammals, showing that large MAFs can induce type IIb myofibers even in humans, with potential applications for enhancing athletic performance and addressing age-related muscle weakness associated with the loss of fast-twitch myofibers.

cell biology↗

bioRxiv2023

Dual-specificity phosphatases 13 and 27 as key switches in muscle stem cell transition from proliferation to differentiation

Muscle regeneration depends on muscle stem cell (MuSC) activity. Myogenic regulatory factors, including myoblast determination protein 1 (MyoD), regulate the fate transition of MuSCs. However, the direct target of MYOD in the process is not completely clear. Using previously established MyoD knock-in (MyoD-KI) mice, we revealed that MyoD targets dual-specificity phosphatase (Dusp) 13 and Dusp27. In Dusp13:Dusp27 double knock-out (DKO) mice, the ability for muscle regeneration after injury was reduced. Moreover, single-cell RNA sequencing of MyoD-high expressing MuSCs from MyoD-KI mice revealed that Dusp13 and Dusp27 are expressed only in specific populations within MyoD-high MuSCs, which also express Myogenin. Overexpressing Dusp13 in MuSCs causes premature muscle differentiation. Thus, we propose a model where DUSP13 and DUSP27 contribute to the fate transition of MuSCs from proliferation to differentiation during myogenesis. Significance StatementMYOD protein is not expressed in quiescent muscle stem cells but accumulates rapidly following muscle injury, leading to the proliferation of myogenic progenitors for differentiation. However, the direct targets of MYOD, aside from myogenin, which play roles in myogenic differentiation remain incompletely understood. Using previously established MyoD knock-in mice and single-cell RNA sequencing, we discovered that Dusp13 and Dusp27 are potential target genes of MYOD that promote myogenesis during muscle regeneration in adult mice.

cell biology↗