PLD regulates myoblast differentiation through the mTOR-IGF2 pathway.
A mammalian target of rapamycin (mTOR) pathway is essential for the differentiation of cultured skeletal myoblasts in response to growth factor withdrawal. Previously, phospholipase D (PLD) has been found to play a role in cell growth regulation and mitogenic activation of mTOR signaling. However, a role for PLD in the autocrine regulation of myoblast differentiation is not known. Here we show that upon induction of differentiation in mouse C2C12 satellite cells, the expression of both PLD1 and PLD2 is upregulated. C2C12 differentiation is markedly inhibited by 1-butanol, an inhibitor of the PLD-catalyzed transphosphatidylation reaction, and also by the knockdown of PLD1, but not PLD2. Further investigation has revealed that PLD1 is unlikely to regulate myogenesis through modulation of the actin cytoskeleton as previously suggested. Instead, PLD1 positively regulates mTOR signaling leading to the production of IGF2, an autocrine factor instrumental for the initiation of satellite cell differentiation. Furthermore, exogenous IGF2 fully rescues the differentiation defect resulting from PLD1 knockdown. Hence, PLD1 is critically involved in skeletal myogenesis by regulating the mTOR-IGF2 pathway.
Yoon
Mee-Sup
MS
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Avenue B107, Urbana, IL 61801, USA.
Chen
Jie
J
D020001:1-Butanol / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development / Q000187:drug effects / Q000502:physiology; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D017931:DNA Primers; D007335:Insulin-Like Growth Factor II; D020001:1-Butanol; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; C106801:phospholipase D1