title: HACD1, a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth.
abstract: The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies, yet the underlying cellular and molecular mechanisms remain elusive. In this study, we investigate the role of HACD1/PTPLA, which is involved in the elongation of the very long chain fatty acids, in muscle fibre formation. In humans and dogs, HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscle weakness. Through analysis of HACD1-deficient Labradors, Hacd1-knockout mice, and Hacd1-deficient myoblasts, we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration. We further demonstrate that in normal differentiating myoblasts, expression of the catalytically active HACD1 isoform, which is encoded by a muscle-enriched splice variant, yields decreased lysophosphatidylcholine content, a potent inhibitor of myoblast fusion, and increased concentrations of ≥ C18 and monounsaturated fatty acids of phospholipids. These lipid modifications correlate with a reduction in plasma membrane rigidity. In conclusion, we propose that fusion impairment constitutes a novel, non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Jordan
authors.initials: J
authors.lastname: Blondelle
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohno
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gache
authors.affiliation: Université de Bourgogne, UMR A 02.102 PAM-EPMB, AgroSup Dijon, 21000 Dijon, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Guyot
authors.affiliation: Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine-Site Broussais, 75015 Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Storck
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard-Gutton
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Barthélémy
authors.affiliation: Comparative Neuromuscular Disease Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London NW1 0TU, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Walmsley
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Anaëlle
authors.initials: A
authors.lastname: Rahier
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gadin
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guillaud
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prola
authors.affiliation: Thérapie des maladies du muscle strié INSERM U974 - CNRS UMR7215 - UPMC UM76 - Institut de Myologie, Université Pierre et Marie Curie - Université Paris Descartes, 75000 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubin-Houzelstein
authors.affiliation: Université de Bourgogne, Faculté des Sciences Gabriel, Bio-PeroxIL, 21000 Dijon, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Demarquoy
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Relaix
authors.affiliation: Comparative Neuromuscular Disease Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, London NW1 0TU, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Piercy
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kihara
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France fstorck@vet-alfort.fr ltiret@vet-alfort.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Tiret
authors.affiliation: Inserm, IMRB U955-E10, 94000 Créteil, France Université Paris-Est, Ecole nationale vétérinaire d'Alfort (EnvA), 94700 Maisons-Alfort, France Université Paris-Est Créteil, Faculté de médecine, 94000 Créteil, France fstorck@vet-alfort.fr ltiret@vet-alfort.fr.
authors.forename: Fanny
authors.initials: F
authors.lastname: Pilot-Storck
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017027:Protein Tyrosine Phosphatases
keywords: LPC; MUFA; PTPLA; VLCFA; centronuclear myopathy