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广东快乐十分预测网:Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program
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Skeletal muscle harbors a robust, yet quiescent stem cell population. These stem cells are activated upon myofiber injury to repair damaged myotome. This regenerative myogenesis is guided by external signaling cues that allow stem cells to acquire various stem cell fates. Here, we describe a growth factor and nutrient-stimulated pathway, whereby mammalian target of rapamycin (mTOR) activates Per–Arnt–Sim domain kinase (PASK) protein kinase in muscle stem cells. This mTOR-dependent activation of PASK is required for the transcriptional induction of the myogenin gene and subsequent terminal differentiation program. Finally, our results suggest that mTOR-PASK and mTOR-S6 Kinase signaling are required for distinct stages of myogenesis program, and link nutrient environment to early stages of the myogenesis program.
During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiation-committed progenitors (early stage of differentiation, marked by the induction of myogenin expression), myotube fusion, and, ultimately, hypertrophy (later stage of differentiation). While a major mTORC1 substrate, p70S6K, is required for myotube fusion and hypertrophy, an mTORC1 effector for the induction of myogenin expression remains unclear. Here, we identified Per–Arnt–Sim domain kinase (PASK) as a downstream phosphorylation target of mTORC1 in MuSCs during differentiation. We have recently shown that the PASK phosphorylates Wdr5 to stimulate MuSC differentiation by epigenetically activating the myogenin promoter. We show that phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exit from self-renewal, and induction of the myogenesis program. Our studies reveal that mTORC1-PASK signaling is required for the rise of myogenin-positive committed myoblasts (early stage of myogenesis), whereas mTORC1-S6K signaling is required for myoblast fusion (later stage of myogenesis). Thus, our discoveries allow molecular dissection of mTOR functions during different stages of the myogenesis program driven by two different substrates.
- ?1To whom correspondence may be addressed. Email: or .
?2Present address: Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
?3Present address: Department of Biochemistry, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY 10065.
Author contributions: C.K.K. and J.R. designed research; C.K.K., X.W., S.F., S.A.W.K., and N.D. performed research; C.K.K., X.W., D.M.S., and J.R. contributed new reagents/analytic tools; C.K.K., X.W., S.P.G., and J.R. analyzed data; and C.K.K. and J.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1804013116/-/DCSupplemental.
Published under the PNAS license.