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

Abstract

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 differentiationcommitted 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. mTOR | PASK | myogenin | muscle stem cell | Pax7

Roles of mTOR Signaling in Tissue Regeneration

“…Ablation of 4EBP1 facilitates myofiber growth, but does not affect the activation of satellite cells [137]. After injury, activation of Per-Arnt-Sim domain kinase (PASK), a downstream phosphorylation target of mTORC1, phosphorylates Wdr5 to induce the expression of myogenin and stimulates MuSCs differentiation into myoblasts [138] (Figure 3C). The mTORC1-S6K pathway is also required for myoblasts fusion to accomplish myofiber formation during muscle regeneration [138].…”

“…After injury, activation of Per-Arnt-Sim domain kinase (PASK), a downstream phosphorylation target of mTORC1, phosphorylates Wdr5 to induce the expression of myogenin and stimulates MuSCs differentiation into myoblasts [138] (Figure 3C). The mTORC1-S6K pathway is also required for myoblasts fusion to accomplish myofiber formation during muscle regeneration [138]. micro-RNAs (miRNAs) have been reported as important modulators of myoblasts formation and fusion during muscle regeneration [139,140,141,142].…”

Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study

“…Both mTORC1 and mTORC2 regulate cellular metabolism, survival, proliferation, and growth. mTORC1 is a central hub for nutrient-sensing and energy metabolism and, as such, coordinates anabolic protein and nucleotide synthesis and catabolic autophagy 9 – 16 . On the other hand, mTORC2 drives insulin signaling by phosphorylating Akt ( Ser473 )/PKB downstream of the phosphoinositide 3-kinase (PI3K)/insulin pathway 17 – 20 .…”

Validation of PAS Kinase, a Regulator of Hepatic Fatty Acid and Triglyceride Synthesis, as a Therapeutic Target for Nonalcoholic Steatohepatitis

“…( 6‐12 ) PASK is posttranslationally activated in response to nutrient and hormonal signals by phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) protein kinase. ( 13 ) Finally, PASK is also regulated by metabolic status at the level of gene expression. ( 7 ) Studies using genetic and pharmacologic approaches have further demonstrated that PASK is required for the proteolytic maturation in mouse and rat liver of sterol regulatory element‐binding protein (SREBP)‐1c, a transcriptional activator of genes that encodes the enzymes that catalyze fatty acid and triglyceride (TG) production.…”