Abstract
ABSTRACTThe 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 Myf6cre 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.
Highlights
The SMYD1 gene encodes an evolutionarily conserved histone methyltransferase containing a catalytic SET domain split by a zincfinger-rich MYND domain
By monitoring yellow fluorescent protein (YFP) fluorescence, we found the onset of Myf6cre-induced recombination to occur at E17.5, being just barely detectable in skeletal muscles at this point
Similar to Smyd1 CKO mice, humans with centronuclear myopathy (CNM) caused by BIN1 mutations often present with hypotrophy, dense oxidative staining in the vicinity of the central nuclei, myofibrillar disorganization and a nonradial sarcoplasmic reticulum pattern
Summary
The SMYD1 gene encodes an evolutionarily conserved histone methyltransferase containing a catalytic SET domain split by a zincfinger-rich MYND domain. The MYND domain is a protein-protein interaction motif best known for its association with histone deacetylase (HDAC)-containing co-repressor complexes (Liu et al, 2007; Lutterbach et al, 1998; Masselink and Bernards, 2000). SMYD1 localizes to the sarcoplasm, where it directly interacts with myosin through its C-terminal region (Just et al, 2011)
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