Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

May 11, 2019Proceedings of the National Academy of Sciences of the United States of America

Activation of PASK by mTORC1 is needed to start the final cell specialization process

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Abstract

Phosphorylation of Per-Arnt-Sim domain kinase (PASK) by mTORC1 is essential for muscle stem cell differentiation and myogenesis.

Muscle stem cells (MuSCs) require mTORC1 signaling for differentiation and hypertrophy.
PASK is identified as a key phosphorylation target of mTORC1 during MuSC differentiation.
Phosphorylated PASK activates transcription and promotes the transition from self-renewal to myogenesis.
mTORC1-PASK signaling is necessary for the increase of myogenin-positive committed myoblasts.
Distinct mTORC1 substrates, PASK and p70S6K, regulate early and late stages of myogenesis.

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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 ofexpression), 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 ofexpression 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 thepromoter. We show that phosphorylation of PASK by mTORC1 is required for the activation oftranscription, 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. myogenin myogenin myogenin myogenin

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Activation of PASK by mTORC1 is required for the onset of the terminal differentiation program

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