Epigenetic Changes Governing Scn5a Expression in Denervated Skeletal Muscle.
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ABSTRACT:
SUBMITTER: Carreras D
PROVIDER: S-EPMC7963191 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Skeletal muscle is a highly plastic tissue and decreased skeletal muscle mass (muscle atrophy) results in deteriorated motor function and perturbed body homeostasis. Myogenin promoter-associated long non-coding RNA (lncRNA) Myoparr promotes skeletal muscle atrophy caused by surgical denervation; however, the precise molecular mechanism remains unclear. Here, we examined the downstream genes of Myoparr during muscle atrophy following denervation of tibialis anterior (TA) muscles in C57BL/6J mice. Myoparr knockdown affected the expression of 848 genes. Sixty-five of the genes differentially regulated by Myoparr knockdown coded secretory proteins. Among these 65 genes identified in Myoparr-depleted skeletal muscles after denervation, we focused on the increased expression of growth/differentiation factor 5 (GDF5), an inhibitor of muscle atrophy. Myoparr knockdown led to activated bone morphogenetic protein (BMP) signaling in denervated muscles, as indicated by the increased levels of phosphorylated Smad1/5/8. Our detailed evaluation of downstream genes of Myoparr also revealed that Myoparr regulated differential gene expression between myogenic differentiation and muscle atrophy. This is the first report demonstrating the in vivo role of Myoparr in regulating BMP signaling in denervated muscles. Therefore, lncRNAs that have inhibitory activity on BMP signaling may be putative therapeutic targets for skeletal muscle atrophy.
| S-EPMC6631233 | biostudies-literature
Project description:Peripheral nerve injury is common, and can lead to skeletal muscle atrophy and dysfunction. However, the underlying molecular mechanisms are not fully understood. The transcription factors have been proved to play a key role in denervated muscle atrophy. In order to systematically analyze transcription factors and obtain more comprehensive information of the molecular regulatory mechanisms in denervated muscle atrophy, a new transcriptome survey focused on transcription factors are warranted. In the current study, we used microarray to identify and analyze differentially expressed genes encoding transcription factors in denervated muscle atrophy in a rat model of sciatic nerve dissection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to explore the biological functions of differentially expressed transcription factors and their target genes related to skeletal muscle pathophysiology. We found that the differentially expressed transcription factors were mainly involved in the immune response. Based on correlation analysis and the expression trends of transcription factors, 18 differentially expressed transcription factors were identified. Stat3, Myod1, Runx1, Atf3, Junb, Runx2, Myf6, Stat5a, Tead4, Klf5, Myog, Mef2a, and Hes6 were upregulated. Ppargc1a, Nr4a1, Lhx2, Ppara, and Rxrg were downregulated. Functional network mapping revealed that these transcription factors are mainly involved in inflammation, development, aging, proteolysis, differentiation, regeneration, autophagy, oxidative stress, atrophy, and ubiquitination. These findings may help understand the regulatory mechanisms of denervated muscle atrophy and provide potential targets for future therapeutic interventions for muscle atrophy following peripheral nerve injury.
| S-EPMC9263185 | biostudies-literature
Project description:To determine the role of denervation and motor unit turnover in the age-related increase in skeletal muscle oxidative stress, the hydrogen peroxide (H2O2) specific, genetically-encoded, fluorescent cyto-HyPer2 probe was expressed in mouse anterior tibialis (AT) muscle and compared with ex vivo measurements of mitochondrial oxidant generation. Crush of the peroneal nerve induced increased mitochondrial peroxide generation, measured in permeabilised AT fibers ex vivo and intra vital confocal microscopy of cyto-HyPer2 fluorescence showed increased cytosolic H2O2 in a sub-set (~24%) of individual fibers associated with onset of fiber atrophy. In comparison, mitochondrial peroxide generation was also increased in resting muscle from old (26 month) mice compared with adult (6-8 month) mice, but no age effect on fiber cytosolic H2O2 in vivo was seen. Thus ageing is associated with an increased ability of muscle fibers to maintain cytosolic redox homeostasis in the presence of denervation-induced increase in mitochondrial peroxide generation.
| S-EPMC6783413 | biostudies-literature
Project description:Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.
| S-EPMC10216238 | biostudies-literature
Project description:Exercise training is continually challenging whole-body homeostasis, leading to improvements in performance and health. Adaptations to exercise training are complex and are influenced by both environmental and genetic factors. Epigenetic factors regulate gene expression in a tissue-specific manner and constitute a link between the genotype and the environment. Moreover, epigenetic factors are emerging as potential biomarkers that could predict the response to exercise training. This systematic review aimed to identify epigenetic changes that have been reported in skeletal muscle following exercise training in healthy populations. A literature search of five databases (PUBMED, MEDLINE, CINHAL, SCOPUS and SportDiscuss) was conducted in November 2018. Articles were included if they examined epigenetic modifications (DNA methylation, histone modifications and non-coding RNAs) in skeletal muscle, following either an acute bout of exercise, an exercise intervention in a pre/post design, or a case/control type of study. Twenty-two studies met the inclusion criteria. Several epigenetic markers including DNA methylation of genes known to be differentially expressed after exercise and myomiRs were reported to be modified after exercise. Several epigenetic marks were identified to be altered in response to exercise, with potential influence on skeletal muscle metabolism. However, whether these epigenetic marks play a role in the physiological impact of exercise is unclear. Exercise epigenetics is still a very young research field, and it is expected that in the future the causality of such changes will be elucidated via the utilization of emerging experimental models able to target the epigenome.
| S-EPMC6557592 | biostudies-literature
Project description:PurposeTo investigate the value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for evaluating denervated skeletal muscle in rabbits.Materials and methods24 male rabbits were randomly divided into an irreversible neurotmesis group and a control group. In the experimental group, the sciatic nerves of rabbits were transected for irreversible neurotmesis model. A sham operation was performed in the control group. MRI of rabbit lower legs was performed before nerve surgery and 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, and 12 weeks after surgery.ResultsSignal intensity changes were seen in the left gastrocnemius muscle on the T2-weighted images. DCE-MRI derived parameters (Ktrans, Kep, and Vp) were measured in vivo. In the irreversible neurotmesis group, T2-weighted images showed increased signal intensity in the left gastrocnemius muscle. Ktrans, Vp values changes occur as early as 1 day after denervation, and increased gradually until 4 weeks after surgery. There are significant increases in both Ktrans and Vp values compared with those in the control group after surgery (P < 0.05). Kep values show no significant difference between the irreversible neurotmesis group and the control group.ConclusionDCE-MRI hold the promise of an early and sensitive diagnosis of denervated skeletal muscle.
| S-EPMC6450635 | biostudies-literature
Project description:BackgroundTransforming growth factor beta 1 (TGF-β1) is a classical modulator of skeletal muscle and regulates several processes, such as myogenesis, regeneration and muscle function in skeletal muscle diseases. Skeletal muscle atrophy, characterized by the loss of muscle strength and mass, is one of the pathological conditions regulated by TGF-β1, but the underlying mechanism involved in the atrophic effects of TGF-β1 is not fully understood.MethodsMice sciatic nerve transection model was created and gastrocnemius were analysed by western blot, immunofluorescence staining and fibre diameter quantification after 2 weeks. Exogenous TGF-β1 was administrated and high-mobility group box-1 (HMGB1), autophagy were blocked by siRNA and chloroquine (CQ) respectively to explore the mechanism of the atrophic effect of TGF-β1 in denervated muscle. Similar methods were performed in C2C12 cells.ResultsWe found that TGF-β1 was induced in denervated muscle and it could promote atrophy of skeletal muscle both in vivo and in vitro, up-regulated HMGB1 and increased autophagy activity were also detected in denervated muscle and were further promoted by exogenous TGF-β1. The atrophic effect of TGF-β1 could be inhibited when HMGB1/autophagy pathway was blocked.ConclusionsThus, our data revealed that TGF-β1 is a vital regulatory factor in denervated skeletal muscle in which HMGB1/ autophagy pathway mediates the atrophic effect of TGF-β1. Our findings confirmed a new pathway in denervation-induced skeletal muscle atrophy and it may be a novel therapeutic target for patients with muscle atrophy after peripheral nerve injury.
| S-EPMC6286536 | biostudies-literature
Project description:BackgroundBeta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood. The objective of this research was to identify novel genes and physiological pathways that potentially facilitate BA induced skeletal muscle growth. The Affymetrix platform was utilized to identify gene expression changes in mouse skeletal muscle 24 hours and 10 days after administration of the BA clenbuterol.ResultsAdministration of clenbuterol stimulated anabolic activity, as indicated by decreased blood urea nitrogen (BUN; P < 0.01) and increased body weight gain (P < 0.05) 24 hours or 10 days, respectively, after initiation of clenbuterol treatment. A total of 22,605 probesets were evaluated with 52 probesets defined as differentially expressed based on a false discovery rate of 10%. Differential mRNA abundance of four of these genes was validated in an independent experiment by quantitative PCR. Functional characterization of differentially expressed genes revealed several categories that participate in biological processes important to skeletal muscle growth, including regulators of transcription and translation, mediators of cell-signalling pathways, and genes involved in polyamine metabolism.ConclusionGlobal evaluation of gene expression after administration of clenbuterol identified changes in gene expression and overrepresented functional categories of genes that may regulate BA-induced muscle hypertrophy. Changes in mRNA abundance of multiple genes associated with myogenic differentiation may indicate an important effect of BA on proliferation, differentiation, and/or recruitment of satellite cells into muscle fibers to promote muscle hypertrophy. Increased mRNA abundance of genes involved in the initiation of translation suggests that increased levels of protein synthesis often associated with BA administration may result from a general up-regulation of translational initiators. Additionally, numerous other genes and physiological pathways were identified that will be important targets for further investigations of the hypertrophic effect of BA on skeletal muscle.
| S-EPMC1766935 | biostudies-literature
Project description:Treatment options for denervated skeletal muscle atrophy are limited, in part because the underlying molecular mechanisms are not well understood. Unlike previous transcriptomics studies conducted in rodent models of peripheral nerve injury, in the present study, we performed high-throughput sequencing with denervated atrophic biceps muscle and normal (non-denervated) sternocleidomastoid muscle samples obtained from four brachial plexus injury (BPI) patients. We also investigated whether Ficus carica L. (FCL.) extract can suppress denervated muscle atrophy in a mouse model, along with the mechanism of action. We identified 1471 genes that were differentially expressed between clinical specimens of atrophic and normal muscle, including 771 that were downregulated and 700 that were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed genes were mainly enriched in the GO terms "structural constituent of muscle," "Z disc," "M band," and "striated muscle contraction," as well as "Cell adhesion molecules," "Glycolysis/Gluconeogenesis," "Peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway," and "P53 signaling pathway." In experiments using mice, the reduction in wet weight and myofiber diameter in denervated muscle was improved by FCL. extract compared to saline administration, which was accompanied by downregulation of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-κB activation and PPARα expression, the degree of NF-κB activation was lower while PPARα and inhibitor of NF-κB IκBα expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPARα expression and inhibiting NF-κB activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.
| S-EPMC7744683 | biostudies-literature
Project description:Alpha-motoneurons and muscle fibres are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy. Postsynaptic neuromuscular junction staining for VAPB was intense in normal human and mouse muscle and decreased in denervated Nmd2J mouse muscle fibres. In contrast, VAPB levels together with other chaperones and autophagy markers were increased in extrasynaptic regions of denervated muscle fibres of patients with MNDs and other NMAs, especially at sites of focal myofibrillar disintegration (targets). These findings did not differ between NMAs due to ALS and other causes. G93A-SOD1 mouse muscle fibres showed a similar pattern of protein level increases in denervated muscle fibres. In addition, they showed globular VAPB-immunoreactive structures together with misfolded SOD1 protein accumulations, suggesting a primary myopathic change. Our findings indicate that altered expression and localization of these ER proteins and autophagy markers are part of the dynamic response of muscle fibres to denervation. The ER is particularly prominent and vulnerable in both muscle fibres and alpha-motoneurons. Thus, ER pathology could contribute to the selective build-up of degenerative changes in the neuromuscular axis in MNDs.
| S-EPMC8029212 | biostudies-literature