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Increased global DNA methylation by Dnmt3a disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity

ABSTRACT: Increased global DNA methylation by Dnmt3a disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity

PROVIDER: PRJNA1091361 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28431748_1.fastq.gz	Fastqsanger.gz
	SRR28431748_2.fastq.gz	Fastqsanger.gz
	SRR28431749_1.fastq.gz	Fastqsanger.gz
	SRR28431749_2.fastq.gz	Fastqsanger.gz
	SRR28431750_1.fastq.gz	Fastqsanger.gz

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Increased global DNA methylation by Dnmt3a disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity

Project description:Loss of muscle mass and function—a hallmark of skeletal muscle aging—is known as sarcopenia. Moreover, mammalian aging is reportedly driven by loss of epigenetic information. However, the effect of epigenetic alterations on skeletal muscle homeostasis is unknown. In this study, we show that chronic elevation of global DNA methylation results in a myopathy-like phenotype and age-related changes in skeletal muscle. Overexpression of muscle de novo methyltransferase 3a (Dnmt3a) increased central nucleus-positive myofibers, predominantly in fast-twitch myofibers, and shifted muscle fiber type to stress-resistant slow-twitch myofibers, accompanied by increased inflammatory and senescent signatures, decreased mitochondrial OXPHOS complex I protein level, and reduced basal autophagy in skeletal muscle. Chronic Dnmt3a overexpression decreased muscle mass and strength, and impaired tolerance to endurance exercise with age. This age-related decline in endurance exercise capacity was accompanied by an augmented inflammatory signature in a manner that is enhanced with age and promoted muscle atrophy. Network analysis identified Akt1 as a potential hub gene. Dnmt3a expression not only reduced sensitivity to starvation-induced muscle atrophy by suppressing the FoxO-regulated autophagy and ubiquitin–proteasome systems, but also reduced the restorability from starvation-induced muscle atrophy. These data suggest that increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related muscle atrophy, and reduces muscle metabolic elasticity.

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Increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity

Project description:Loss of muscle mass and function—a hallmark of skeletal muscle aging—is known as sarcopenia. Moreover, mammalian aging is reportedly driven by loss of epigenetic information. However, the effect of epigenetic alterations on skeletal muscle homeostasis is unknown. In this study, we show that chronic elevation of global DNA methylation results in a myopathy-like phenotype and age-related changes in skeletal muscle. Overexpression of muscle de novo methyltransferase 3a (Dnmt3a) increased central nucleus-positive myofibers, predominantly in fast-twitch myofibers, and shifted muscle fiber type to stress-resistant slow-twitch myofibers, accompanied by upregulation of chemokine and immune system-related genes and reduced basal autophagy in skeletal muscle. Dnmt3a overexpression reduced muscle androgen receptor signaling, decreased muscle mass and strength, and impaired tolerance to endurance exercise with age. Network analysis identified Akt1 as a potential hub gene. Dnmt3a expression reduced sensitivity to starvation-induced muscle atrophy by suppressing the FoxO-regulated autophagy and ubiquitin–proteasome systems. These data suggest that increased global DNA methylation disrupts skeletal muscle homeostasis, promotes age-related decline in muscle function, and reduces muscle plasticity.

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Microarray analysis of satellite cells in Dnmt3a knockout mice

Project description:DNA methylation occurs as 5-methylcytosines mainly at cytosine-guanine dinucleotides, so-called CpG sites, and such methylation is a well-studied epigenetic mechanism for transcriptional regulation. Generally, DNA methylation of the gene promoter is correlated with transcriptional repression. Genomic DNA methylation patterns are established by the actions of the de novo methyltransferases Dnmt3a and Dnmt3b, and are maintained by the methyltransferase Dnmt1. Expression of Dnmt3a mRNA is relatively high in skeletal muscle, suggesting a major role in transcriptional regulation. Also, denervation of skeletal muscle decreased expression of Dnmt3a mRNA, suggesting involvement of Dnmt3a in pathophysiology during atrophy. Decreased regeneration capacity in atrophied skeletal muscle hampers muscle mass recovery after injury and the impaired muscle function, lowers the quality of life. We found that in skeletal muscle of atrophy models, Dnmt3a was decreased. Muscle regeneration was delayed in the skeletal muscle-specific Dnmt3a knockout (Dnmt3a-KO) mice, in which Dnmt3a was deleted in skeletal muscle as well as in satellite cells, important for muscle regeneration. In this study, we used Dnmt3a-KO mice, and attempt to clarify the mechanism of reduced muscle regeneration during atrophy. The microarray data shows that expression of a Gdf/Bmp family protein Gdf5, which suppressed differentiation of satellite cells, is activated in Dnmt3a-KO mice compared with wild-type mice.

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Project description:The hypothesis tested was that loss of Ndst1 in smooth muscle would lead to significant changes in gene expression and alter functional properties in large and small vessels. The increase in aortic elasticity was increased in mice lacking Ndst1 was associated with significant changes in genes that modify mechano-sensing, contractility and elasticity. Total RNA extracted from aorta from smooth muscle specific Ndst1 deficient mice (SM22αcre+Ndst1-/-) was compared to aorta from wild type (WT, SM22αcre-Ndst1wt/wt ) control mice.

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Gadd45a Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4

Project description:Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle fiber proteins that associate with Gadd45a as it induces skeletal muscle atrophy in living mice. We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, the MAP kinase kinase kinase MEKK4. Furthermore, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into way that skeletal muscle atrophy occurs at the molecular level.

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Smooth muscle specific deletion of N-deacetylase-N-sulfotransferase 1 (Ndst1) results in increased arterial elasticity in mice

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Microarray analysis of transgenic mice specifically overexpressing Dnmt3a in skeletal muscle (Dnmt3a Tg mice)

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Project description:Sepsis-induced skeletal muscle atrophy is common in septic patients with the increases risk of mortality and is associated with myocellular mitochondrial dysfunction. Nevertheless, the specific mechanism of sepsis muscle atrophy remains unclear. Here we conducted a clinical retrospective analysis and observed the elevation of skeletal muscle index (ΔSMI) was an independent risk factor for 60-day mortality in septic patients. Moreover, in mouse model of sepsis, the skeletal muscle atrophy was also observed, which was associated with the upregulation of S100a8/a9-mediated mitochondrial dysfunction. Inhibition of S100a8/a9 significantly improved mitochondrial function and alleviated muscle atrophy. Conversely, administration of recombinant S100a8/a9 protein exacerbated mitochondrial energy exhaustion and myocyte atrophy. Mechanistically, S100a8/a9 binding to RAGE induced Drp1 phosphorylation and mitochondrial fragmentation, resulting in muscle atrophy. Additionally, RAGE ablation or administration of Drp1 inhibitor significantly reduced Drp1-mediated mitochondrial fission, improved mitochondrial morphology and function. Our findings indicated the pivotal role of S100a8/a9 in driving the mitochondrial fragmentation in septic muscle atrophy. Targeting S100a8/a9-RAGE-initiated mitochondrial fission might offer a promising therapeutic intervention against septic muscle atrophy. Taken together, our data provide a potential mechanism for sepsis-induced muscle atrophy.

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