Progressive Structural Defects in Canine Centronuclear Myopathy Indicate a Role for HACD1 in Maintaining Skeletal Muscle Membrane Systems
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- 作者：Gemma L. Walmsley&lowast ; ; glw22@liv.ac.uk ; Sté ; phane Blot&dagger ; ; &Dagger ; ; Kerrie Venner§ ; ; Caroline Sewry¶ ; ; Jocelyn Laporte‖ ; Jordan Blondelle&dagger ; ; &Dagger ; ; Inè ; s Barthé ; lé ; my&dagger ; ; &Dagger ; ; Marie Maurer&dagger ; ; &Dagger ; ; Nicolas Blanchard-Gutton&dagger ; ; &Dagger ; ; Fanny Pilot-Storck&dagger ; ; &Dagger ; ; Laurent Tiret&dagger ; ; &Dagger ; ; Richard J. Piercy&lowast ;
- 刊名：The American Journal of Pathology
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：187
- 期：2
- 页码：441-456
- 全文大小：5675 K
- 卷排序：187
文摘
Mutations in HACD1/PTPLA cause recessive congenital myopathies in humans and dogs. Hydroxyacyl-coA dehydratases are required for elongation of very long chain fatty acids, and HACD1 has a role in early myogenesis, but the functions of this striated muscle-specific enzyme in more differentiated skeletal muscle remain unknown. Canine HACD1 deficiency is histopathologically classified as a centronuclear myopathy (CNM). We investigated the hypothesis that muscle from HACD1-deficient dogs has membrane abnormalities in common with CNMs with different genetic causes. We found progressive changes in tubuloreticular and sarcolemmal membranes and mislocalized triads and mitochondria in skeletal muscle from animals deficient in HACD1. Furthermore, comparable membranous abnormalities in cultured HACD1-deficient myotubes provide additional evidence that these defects are a primary consequence of altered HACD1 expression. Our novel findings, including T-tubule dilatation and disorganization, associated with defects in this additional CNM-associated gene provide a definitive pathophysiologic link with these disorders, confirm that dogs deficient in HACD1 are relevant models, and strengthen the evidence for a unifying pathogenesis in CNMs via defective membrane trafficking and excitation-contraction coupling in muscle. These results build on previous work by determining further functional roles of HACD1 in muscle and provide new insight into the pathology and pathogenetic mechanisms of HACD1 CNM. Consequently, alterations in membrane properties associated with HACD1 mutations should be investigated in humans with related phenotypes.