HACD1, a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth.
HACD1, a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth.
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DOI：
10.1093/jmcb/mjv049
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发表时间：
2015-10
影响因子：
5.5
通讯作者：
Pilot-Storck F
中科院分区：
文献类型：
--
作者：
Blondelle J;Ohno Y;Gache V;Guyot S;Storck S;Blanchard-Gutton N;Barthélémy I;Walmsley G;Rahier A;Gadin S;Maurer M;Guillaud L;Prola A;Ferry A;Aubin-Houzelstein G;Demarquoy J;Relaix F;Piercy RJ;Blot S;Kihara A;Tiret L;Pilot-Storck F
骨骼肌肌纤维直径的减小是几种先天性肌病的标志，但其潜在的细胞和分子机制仍然难以捉摸。在这项研究中，我们调查的作用，HACD 1/PTPLA，这是参与延长的非常长的链脂肪酸，在肌纤维的形成。在人类和狗中，HACD 1缺乏导致先天性肌病，纤维大小不成比例，伴有全身性肌无力。通过分析HACD 1缺陷的拉布拉多犬，HACD 1基因敲除小鼠，HACD 1缺陷的成肌细胞，我们提供的证据表明，HACD 1促进肌肉发育和再生过程中的成肌细胞融合。我们进一步证明，在正常分化的成肌细胞中，由富含肌肉的剪接变体编码的催化活性HACD 1同种型的表达降低了溶血磷脂酰胆碱含量，这是成肌细胞融合的有效抑制剂，并增加了磷脂中≥C18和单不饱和脂肪酸的浓度。这些脂质修饰与质膜刚性的降低相关。总之，我们提出，融合障碍构成了一种新的，非排他性的病理机制，在先天性肌病的运作，并揭示了HACD 1是一个关键的调节器的脂质依赖性肌纤维生长机制。
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.