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HACD1 , a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth

Jordan Blondelle 1 Yusuke Ohno 2 Vincent Gache 1 Stéphane Guyot 3 Sébastien Storck 4 Nicolas Blanchard-Gutton 1 Inès Barthélémy 1 Gemma Walmsley 1 Anaëlle Rahier 1 Stéphanie Gadin 1 Marie Maurer 1 Laurent Guillaud 1 Alexandre Prola 1 Arnaud Ferry 5 Geneviève Aubin-Houzelstein 1 Jean Demarquoy 6 Frédéric Relaix 1 Richard Piercy 7 Stéphane Blot 1 Akio Kihara 2 Laurent Tiret 1 Fanny Pilot-Storck 1
1 IMRB - Institut Mondor de Recherche Biomédicale
2 Hokkaido University [Sapporo, Japan]
3 PMB - Procédés Microbiologiques et Biotechnologiques
PAM - Procédés Alimentaires et Microbiologiques, PAM - Procédés Alimentaires et Microbiologiques [Dijon]
4 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
5 Thérapie des maladies du muscle strié
6 UB - Université de Bourgogne
7 Comparative Neuromuscular Diseases Laboratory
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.
Keywords : LPC Centronuclear myopathy MUFA PTPLA VLCFA
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Jordan Blondelle, Yusuke Ohno, Vincent Gache, Stéphane Guyot, Sébastien Storck, et al.. HACD1 , a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth. Journal of molecular cell biology, Oxford UP, 2015, 7 (5), pp.429-440. ⟨10.1093/jmcb/mjv049⟩. ⟨hal-02290631⟩

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