title: Mouse myofibers lacking the SMYD1 methyltransferase are susceptible to atrophy, internalization of nuclei and myofibrillar disarray.
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.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA dstewart@uh.edu.
authors.forename: M David
authors.initials: MD
authors.lastname: Stewart
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Suhujey
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Harika
authors.initials: H
authors.lastname: Nagandla
authors.affiliation: Department of Computer Science and Engineering Technology, University of Houston-Downtown, Houston, TX 77002, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Soibam
authors.affiliation: Stem Cell Engineering Department, Texas Heart Institute at St Luke's Episcopal Hospital, Houston, TX 77030, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Benham
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Valenzuela
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: College of Optometry, University of Houston, Houston, TX 77204, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Burns
authors.affiliation: Department of Molecular Physiology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Rasmussen
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.affiliation: 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.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D008297:Male; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000648:ultrastructure; D009124:Muscle Proteins / Q000378:metabolism*; D053580:Muscle Strength; D009133:Muscular Atrophy / Q000201:enzymology* / Q000473:pathology; D009210:Myofibrils / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D009929:Organ Size; D010084:Oxidation-Reduction; D012038:Regeneration; D012508:Sarcolemma / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C096485:Smyd1 protein, mouse; D014157:Transcription Factors
keywords: Development; Genetics; Methylation; Muscle; Myocyte; Myopathy; SMYD1