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 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.

Loss of SMYD1 Results in Perinatal Lethality via Selective Defects within Myotonic Muscle Descendants

“…If so, the data indicate that SMYD1 is not required for skeletal muscle function per se but is essential for maintaining the development and differentiation of skeletal muscle. This is supported by the Myf6-Cre data reported previously [12,13] and noted below.…”

“…While SMYD1 function in the early developing heart has been well documented [3,5,11], its function in early skeletal myogenesis is less understood. By employing Myf6-Cre , we ablated Smyd1 following myofiber differentiation in skeletal myocytes [12,13]. Mutant mice appeared normal through gestation, but when examined ~6 weeks postnatally, they exhibited a phenotype similar to non-degenerative myopathy.…”

Loss of zebrafish Smyd1a interferes with myofibrillar integrity without triggering the misfolded myosin response

“…In mice, a global Smyd1 knock-out results in severe developmental heart defects leading to embryonic lethality [13]. Additionally, conditional Smyd1 deficiency in skeletal myocytes led to severe muscle weakness, myofiber hypotrophy and myofibrillar disarray, substantiating the essential role of Smyd1 in skeletal muscle cells [14]. Due to a genome duplication event, the zebrafish has two Smyd1 genes and one of the two paralogues, Smyd1b, was shown to be crucial for heart and fasttwitch muscle structure and function [3], [5].…”

A compact unc45b‐promoter drives muscle‐specific expression in zebrafish and mouse

“…genesis 54: 431-438, 2016431-438, . V C 2016 In the context of heart and skeletal muscle disorders, the SET and MYND domain containing protein 1 (SMYD1) was identified as disease causing when mutated or defective (Abaci et al, 2010;Gottlieb et al, 2002;Just et al, 2011;Nagandla et al, 2016;Stewart et al, 2016). SMYD1 is exclusively expressed in cardiac and skeletal muscle cells from zebrafish and mice (Just et al, 2011;Nagandla et al, 2016) where it locates to the cell nucleus, as expected for a histone methyltransferase (HMT), and to the sarcomeric M-band (Just et al, 2011).…”