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Dis Model Mech. 2016 Mar;9(3):347-59. doi: 10.1242/dmm.022491.

Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray.

Author information

1
Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA dstewart@uh.edu.
2
Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
3
Department of Computer Science and Engineering Technology, University of Houston-Downtown, Houston, TX 77002, USA.
4
Stem Cell Engineering Department, Texas Heart Institute at St Luke's Episcopal Hospital, Houston, TX 77030, USA.
5
College of Optometry, University of Houston, Houston, TX 77204, USA.
6
Department of Molecular Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Molecular Biosciences, Institute for Cellular Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
8
Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA Stem Cell Engineering Department, Texas Heart Institute at St Luke's Episcopal Hospital, Houston, TX 77030, USA.

Abstract

The Smyd1 gene encodes a lysine methyltransferase specifically expressed in striated muscle. Because Smyd1-null mouse embryos die from heart malformation prior to formation of skeletal muscle, we developed a Smyd1 conditional-knockout allele to determine the consequence of SMYD1 loss in mammalian skeletal muscle. Ablation of SMYD1 specifically in skeletal myocytes after myofiber differentiation using Myf6(cre) produced a non-degenerative myopathy. Mutant mice exhibited weakness, myofiber hypotrophy, prevalence of oxidative myofibers, reduction in triad numbers, regional myofibrillar disorganization/breakdown and a high percentage of myofibers with centralized nuclei. Notably, we found broad upregulation of muscle development genes in the absence of regenerating or degenerating myofibers. These data suggest that the afflicted fibers are in a continual state of repair in an attempt to restore damaged myofibrils. Disease severity was greater for males than females. Despite equivalent expression in all fiber types, loss of SMYD1 primarily affected fast-twitch muscle, illustrating fiber-type-specific functions for SMYD1. This work illustrates a crucial role for SMYD1 in skeletal muscle physiology and myofibril integrity.

KEYWORDS:

Development; Genetics; Methylation; Muscle; Myocyte; Myopathy; SMYD1

PMID:
26935107
PMCID:
PMC4833328
DOI:
10.1242/dmm.022491
[Indexed for MEDLINE]
Free PMC Article

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