Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3

Cenik, Bercin Kutluk; Garg, Ankit; McAnally, John; Shelton, John M.; Richardson, James A.; Bassel‐Duby, Rhonda; Olson, Eric N.; Liu, Ning

doi:10.1172/jci80115

Cited by 48 publications

(62 citation statements)

References 56 publications

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“…and Lmod3 mRNAs were detected in all striated muscles, in agreement with previous studies (Cenik et al, 2015;Chereau et al, 2008;Conley et al, 2001;Nworu et al, 2015;Tian et al, 2015;Yuen et al, 2014), but an unexpected muscle type dependence was observed, with Lmod2 mRNA predominating in slow-twitch soleus, diaphragm, and left ventricular muscles and Lmod3 mRNA more highly expressed than Lmod2 mRNA in fast-twitch TA muscle (Fig. 1C).…”

Section: Gene Expression and Protein Abundance Of Sarcomeric Tmodssupporting

confidence: 92%

“…Preferential Tmod4-Lmod3 and Tmod1-Lmod2 co-expression is also supported by previous findings: (1) Lmod3 is the predominant Lmod isoform in skeletal muscle, in which skeletal myofibrils contain predominantly Tmod4 on thin filament pointed ends (this study; Cenik et al, 2015); (2) Lmod2 is the predominant Lmod isoform in cardiac muscle, in which cardiac myofibrils contain solely Tmod1 on thin filament pointed ends (Chereau et al, 2008;Conley et al, 2001;Gokhin and Fowler, 2011b;SkwarekMaruszewska et al, 2010); (3) LMOD3-deficient nemaline myopathy patients exhibit dramatic loss of TMOD4 protein (Yuen et al, 2014). Although the genetic circuitry regulating preferential Tmod4-Lmod3 and Tmod1-Lmod2 co-expression remains unknown, a possible candidate is the myocardin-related transcription factor (MRTF)/Srf pathway, which has been proposed to activate muscle-specific genes via a feedback loop initiated by Lmod3-mediated actin polymerization and depletion of soluble actin (Cenik et al, 2015). It is conceivable that coexpression of Tmod4-Lmod3 versus Tmod1-Lmod2 leads to different soluble actin levels, leading to different extents of MRTF activation and Srf and Mef2 activity, and expression of skeletal versus cardiac combinations of cytoskeletal genes.…”

Section: Relationship Between Tmods and Lmods In Striated Musclessupporting

confidence: 91%

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Tropomodulin1 directly controls thin filament length in both wild-type and tropomodulin4-deficient skeletal muscle

et al. 2015

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The sarcomeric tropomodulin (Tmod) isoforms Tmod1 and Tmod4 cap thin filament pointed ends and functionally interact with the leiomodin (Lmod) isoforms Lmod2 and Lmod3 to control myofibril organization, thin filament lengths, and actomyosin crossbridge formation in skeletal muscle fibers. Here, we show that Tmod4 is more abundant than Tmod1 at both the transcript and protein level in a variety of muscle types, but the relative abundances of sarcomeric Tmods are muscle specific. We then generate Tmod4 −/− mice, which exhibit normal thin filament lengths, myofibril organization, and skeletal muscle contractile function owing to compensatory upregulation of Tmod1, together with an Lmod isoform switch wherein Lmod3 is downregulated and Lmod2 is upregulated. However, RNAi depletion of Tmod1 from either wild-type or Tmod4 −/− muscle fibers leads to thin filament elongation by ∼15%. Thus, Tmod1 per se, rather than total sarcomeric Tmod levels, controls thin filament lengths in mouse skeletal muscle, whereas Tmod4 appears to be dispensable for thin filament length regulation. These findings identify Tmod1 as the key direct regulator of thin filament length in skeletal muscle, in both adult muscle homeostasis and in developmentally compensated contexts.

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Section: Gene Expression and Protein Abundance Of Sarcomeric Tmodssupporting

confidence: 92%

Section: Relationship Between Tmods and Lmods In Striated Musclessupporting

confidence: 91%

Tropomodulin1 directly controls thin filament length in both wild-type and tropomodulin4-deficient skeletal muscle

et al. 2015

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“…On the other hand, human mutations in LMOD3 are linked to nemaline myopathy (20), a complex congenital skeletal muscle disease characterized by rod-like nemaline bodies that are thought to cause muscle weakness (27,28). Similar to humans with mutations in LMOD3, mice in which Lmod3 has been genetically knocked out exhibit skeletal muscle weakness and the presence of nemaline bodies (29,30). Notably, similar rod-like structures representing elongated dense bodies were frequently seen in visceral smooth muscle of Lmod1-null mice.…”

Section: Discussionmentioning

confidence: 99%

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Halim

Wilson

Oliver

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal–contractile coupling.

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“…We had also previously identified the genes encoding Hspb7 (a small heat shock protein) and Lmod3 (tropomodulin family member) as MEF2 target genes in cardiac muscle (Wales et al, 2014). Human nemaline myopathy has been associated with mutations in Lmod3 (Cenik et al, 2015;Garg et al, 2014;Yuen et al, 2014). Hspb7 expression is higher in mdx (a genetic model of muscular dystrophy) mice than in normal mice and is also enhanced in ageing muscle (Doran et al, 2006(Doran et al, , 2007.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy

Tobin

Yang

Girgis

et al. 2016

Journal of Cell Science

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Mycocyte enhancer factor 2 (MEF2) and activator protein 1 (AP-1) transcription complexes have been individually implicated in myogenesis, but their genetic interaction has not previously been addressed. Using MEF2A, c-Jun and Fra-1 chromatin immunoprecipitation sequencing (ChIP-seq) data and predicted AP-1 consensus motifs, we identified putative common MEF2 and AP-1 target genes, several of which are implicated in regulating the actin cytoskeleton. Because muscle atrophy results in remodelling or degradation of the actin cytoskeleton, we characterized the expression of putative MEF2 and AP-1 target genes (Dstn, Flnc, Hspb7, Lmod3 and Plekhh2) under atrophic conditions using dexamethasone (Dex) treatment in skeletal myoblasts. Heat shock protein b7 (Hspb7) was induced by Dex treatment and further analyses revealed that loss of MEF2A using siRNA prevented Dexregulated induction of Hspb7. Conversely, ectopic Fra-2 or c-Jun expression reduced Dex-mediated upregulation of Hspb7 whereas AP-1 depletion enhanced Hspb7 expression. In vivo, expression of Hspb7 and other autophagy-related genes was upregulated in response to atrophic conditions in mice. Manipulation of Hspb7 levels in mice also impacted gross muscle mass. Collectively, these data indicate that MEF2 and AP-1 confer antagonistic regulation of Hspb7 gene expression in skeletal muscle, with implications for autophagy and muscle atrophy.

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Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3

Cited by 48 publications

References 56 publications

Tropomodulin1 directly controls thin filament length in both wild-type and tropomodulin4-deficient skeletal muscle

Tropomodulin1 directly controls thin filament length in both wild-type and tropomodulin4-deficient skeletal muscle

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy

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