Epigenetics: DNA demethylation promotes skeletal myotube maturation

Hupkes, Marlinda; Jonsson, Malin K.B.; Scheenen, Wim J.J.M.; Rotterdam, Walter van; Sotoca, Ana M.; Someren, Eugene P. van; Heyden, Marcel A.G. van der; Veen, Toon A van; Os, Roselinde I. van Ravestein-van; Bauerschmidt, Susanne; Piek, Ester; Ypey, Dirk L.; Zoelen, Everardus J. van; Dechering, Koen J.

doi:10.1096/fj.11-186122

Cited by 60 publications

(53 citation statements)

References 74 publications

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“…Noteworthy, treatment of myoblasts with the DNA methylation inhibitor 5-azacytidine was shown to promote myogenesis (19), which is consistent with our observation that the majority of growth-and differentiation-related genes in our list show decreased methylation.…”

Section: E917 Exercise Training Alters Dna Methylation Patternssupporting

confidence: 91%

Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice

Kanzleiter

Jähnert

Schulze

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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The adaptive response of skeletal muscle to exercise training is tightly controlled and therefore requires transcriptional regulation. DNA methylation is an epigenetic mechanism known to modulate gene expression, but its contribution to exercise-induced adaptations in skeletal muscle is not well studied. Here, we describe a genome-wide analysis of DNA methylation in muscle of trained mice ( n = 3). Compared with sedentary controls, 2,762 genes exhibited differentially methylated CpGs ( P < 0.05, meth diff >5%, coverage >10) in their putative promoter regions. Alignment with gene expression data ( n = 6) revealed 200 genes with a negative correlation between methylation and expression changes in response to exercise training. The majority of these genes were related to muscle growth and differentiation, and a minor fraction involved in metabolic regulation. Among the candidates were genes that regulate the expression of myogenic regulatory factors ( Plexin A2) as well as genes that participate in muscle hypertrophy ( Igfbp4) and motor neuron innervation ( Dok7). Interestingly, a transcription factor binding site enrichment study discovered significantly enriched occurrence of CpG methylation in the binding sites of the myogenic regulatory factors MyoD and myogenin. These findings suggest that DNA methylation is involved in the regulation of muscle adaptation to regular exercise training.

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Section: E917 Exercise Training Alters Dna Methylation Patternssupporting

confidence: 91%

Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice

Kanzleiter

Jähnert

Schulze

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…To confirm that Dppa2 transcription is regulated by DNA methylation in myoblasts, we treated C2C12 cells with 5-Aza. Expectedly, the treatment induced Dppa2 expression ( Figure 5A); as a positive control, myogenin gene was also induced as previously reported [23]. Several CpG sites were identified in two regions of Dppa2 promoter by computational prediction (EMBOSS Cpgplot; http://www.ebi.ac.uk) ( Figure 5B).…”

Section: Dum Silences Dppa2 Expression Through Recruiting Dnmts To Itsupporting

confidence: 81%

LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration

et al. 2015

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Emerging studies document the roles of long non-coding RNAs (LncRNAs) in regulating gene expression at chromatin level but relatively less is known how they regulate DNA methylation. Here we identify an lncRNA, Dum (developmental pluripotency-associated 2 (Dppa2) Upstream binding Muscle lncRNA) in skeletal myoblast cells. The expression of Dum is dynamically regulated during myogenesis in vitro and in vivo. It is also transcriptionally induced by MyoD binding upon myoblast differentiation. Functional analyses show that it promotes myoblast differentiation and damage-induced muscle regeneration. Mechanistically, Dum was found to silence its neighboring gene, Dppa2, in cis through recruiting Dnmt1, Dnmt3a and Dnmt3b. Furthermore, intrachromosomal looping between Dum locus and Dppa2 promoter is necessary for Dum/Dppa2 interaction. Collectively, we have identified a novel lncRNA that interacts with Dnmts to regulate myogenesis.

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“…The C2C12 mouse myotubes used in the present study display similarities to skeletal muscle, such as the expression of metabolic, myogenic, and sarcomeric proteins, and similarities in their response to anabolic and catabolic compounds (5,32,49). C2C12 myotubes can spontaneously contract; however, they lack neural innervation and the contractile synchronicity of multiple muscle fibers (18). Therefore, the effect of STARS as a regulator of protein synthesis was investigated under basal conditions and following intracellular anabolic and catabolic stress.…”

Section: Discussionmentioning

confidence: 92%

Striated muscle activator of Rho signaling is required for myotube survival but does not influence basal protein synthesis or degradation

Wallace

Russell

2013

American Journal of Physiology-Cell Physiology

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Skeletal muscle mass is regulated by sensing and transmitting extracellular mechanical stress signals to intracellular signaling pathways controlling protein synthesis and degradation. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein that is sensitive to extracellular stress signals. STARS stimulates actin polymerization and influences serum response factor (SRF) and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α transcription of genes involved in muscle growth, structure, and contraction. The role of STARS in skeletal muscle cells is not well understood. This study investigated whether STARS influenced C2C12 myotube growth by regulating protein synthesis and degradation. The influence of STARS on Pgc-1α, Srf, and Errα mRNA levels, as well as several of their downstream targets involved in muscle cell growth, contraction, and metabolism, was also investigated. STARS overexpression increased actin polymerization, with no effect on protein synthesis, protein degradation, or Akt phosphorylation. STARS overexpression increased Pgc-1α, Srf, Ckmt2, Cpt-1β, and Mhc1 mRNA. STARS knockdown reduced actin polymerization and increased cell death and dead cell protease activity. It also increased markers of inflammation (Casp1, Il-1β, and Mcp-1), regeneration (Socs3 and Myh8), and fast myosin isoforms (Mhc2a and Mhc2x). We show for the first time in muscle cells that STARS overexpression increases actin polymerization and shifts the muscle cell to a more oxidative phenotype. The suppression of STARS causes cell death and increases markers of necrosis, inflammation, and regeneration. As STARS levels are suppressed in clinical models associated with increased necrosis and inflammation, such as aging and limb immobilization, rescuing STARS maybe a future therapeutic strategy to maintain skeletal muscle function and attenuate contraction-induced muscle damage.

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Epigenetics: DNA demethylation promotes skeletal myotube maturation

Cited by 60 publications

References 74 publications

Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice

Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice

LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration

Striated muscle activator of Rho signaling is required for myotube survival but does not influence basal protein synthesis or degradation

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