title: Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration.
abstract: Myoblast differentiation and fusion is a well-orchestrated multistep process that is essential for skeletal muscle development and regeneration. Phospholipase D1 (PLD1) has been implicated in the initiation of myoblast differentiation in vitro. However, whether PLD1 plays additional roles in myoblast fusion and exerts a function in myogenesis in vivo remains unknown. Here we show that PLD1 expression is up-regulated in myogenic cells during muscle regeneration after cardiotoxin injury and that genetic ablation of PLD1 results in delayed myofiber regeneration. Myoblasts derived from PLD1-null mice or treated with PLD1-specific inhibitor are unable to form mature myotubes, indicating defects in second-phase myoblast fusion. Concomitantly, the PLD1 product phosphatidic acid is transiently detected on the plasma membrane of differentiating myocytes, and its production is inhibited by PLD1 knockdown. Exogenous lysophosphatidylcholine, a key membrane lipid for fusion pore formation, partially rescues fusion defect resulting from PLD1 inhibition. Thus these studies demonstrate a role for PLD1 in myoblast fusion during myogenesis in which PLD1 facilitates the fusion of mononuclear myocytes with nascent myotubes.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China phuang@enders.tch.harvard.edu szteng@yahoo.com.
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Teng
authors.affiliation: University Hospital and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.affiliation: Department of Pharmacology, Stony Brook University, Stony Brook, NY 11794.
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Tsunaki
authors.initials: T
authors.lastname: Hongu
authors.affiliation: Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
authors.affiliation: University Hospital and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Department of Pharmacology, Stony Brook University, Stony Brook, NY 11794.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.affiliation: The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, China Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115 phuang@enders.tch.harvard.edu szteng@yahoo.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002459:Cell Fusion; D004179:Cobra Cardiotoxin Proteins / Q000633:toxicity; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000502:physiology*; D032448:Myoblasts, Skeletal / Q000201:enzymology / Q000502:physiology*; D010739:Phospholipase D / Q000235:genetics* / Q000502:physiology; D012038:Regeneration; D015854:Up-Regulation
chemical_list: D004179:Cobra Cardiotoxin Proteins; D010739:Phospholipase D; C106801:phospholipase D1