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Project description:Analysis of gene expression patterns in denervated muscle atrophy
| PRJNA828097 | ENA
Project description:To elaborate the process of denervated muscular atrophy, and provide scientific basis for the prevention and treatment of denervated muscular atrophy. we performed a time course transcriptomic analysis of denervated muscular atrophy
2019-06-16 | E-MTAB-8009 | biostudies-arrayexpress
Project description:In skeletal muscle, the pattern of electrical activity regulates the expression of proteins involved in synaptic transmission, contraction and metabolism. Disruptions in electrical activity, resulting from prolonged bed-rest, cast-immobilization or trauma, inevitably lead to muscle atrophy. The mechanisms that regulate muscle atrophy are poorly understood, but it seems likely that changes in gene expression play a key role in initiating and maintaining a muscle atrophy program. Previously, we found that Runx1, a transcription factor previously termed AML1, was substantially induced in muscle following denervation. More recently, we sought to determine whether this increase in Runx1 expression may be causally related to the morphological changes in skeletal muscle that accompany muscle disuse, notably muscle atrophy. We found that Runx1 is indeed required to sustain muscle and to minimize atrophy following denervation. Experiments described here are designed to identify the genes that are regulated by Runx1 in skeletal muscle with the particular goal of identifying genes that regulate muscle atrophy. We propose to use microarray analysis to identify genes, expressed in skeletal muscle, that are mis-regulated in mice lacking Runx1. We inactivated runx1 selectively in skeletal muscle and found that denervated myofibers in mutant mice atrophy far more (90% atrophy) than in wild-type mice (30% atrophy). We therefore reason that Runx1 activates and/or represses genes that are required to sustain muscle and to minimize atrophy. We generated MCK::cre; runx1f/- and runx1f/- control mice. In normal mice, an increase in runx1 expression is detected by two days after denervation and is maximal by five days after denervation. Muscle atrophy is first evident between one and two weeks after denervation. As we wish to avoid detecting global changes in gene expression that are associated with late stages of muscle atrophy, we plan to denervate muscle for three or five days and to compare gene expression in dissected innervated and denervated muscles from mutant and control mice. We will generate thirty samples for comparison-5 replicates per condition: Samples 1-3 from runx1f/- control mice. (1) innervated tibialis anterior muscles (TA); (2) 3-day-denervated TA; (3) 5-day-denervated TA. Samples 4-6 from MCK::cre; runx1f/- mice. (4) innervated TA; (5) 3-day-denervated TA; (6) 5-day-denervated TA. We obtain sufficient total RNA (10 micrograms) from each dissected muscle to avoid pooling samples. We will analyze adult mice of the same age (~six weeks after birth; most will be littermates) and sex-male. It is difficult to anticipate how many genes will be identified in this screen, as few target genes for Runx1 have been identified in any cell type and none in skeletal muscle. Moreover, although we would prefer to focus our attention on genes that are strongly dependent upon Runx1 expression (e.g. more than 5-fold difference in expression in wild-type and mutant mice), we do not know the extent to which target gene expression will depend upon Runx1. For these reasons, in these experiments, we will analyze expression from five âidenticalâ samples, so that we can be confident that even small (e.g. three-fold) differences in expression can be reliably determined. Importantly, in order to confirm results obtained from the microarray data, we will use other assays (RNase protection) to measure RNA expression of candidate genes in innervated and denervated muscles of wild-type and mutant mice.
2008-06-13 | E-GEOD-4411 | biostudies-arrayexpress
Project description:Recent evidence has shown a crucial role for the osteoprotegerin/receptor activator of nuclear factor κ-B ligand/RANK (OPG/RANKL/RANK) signaling axis not only in bone but also in muscle tissue; however, there is still a lack of understanding of its effects on muscle atrophy. Here, we found that denervated Opg knockout mice displayed better functional recovery and delayed muscle atrophy, especially in a specific type IIB fiber. Moreover, OPG deficiency promoted milder activation of the ubiquitin-proteasome pathway, which further verified the protective role of Opg knockout in denervated muscle damage. Furthermore, transcriptome sequencing indicated that Opg knockout upregulated the expression of Inpp5k, Rbm3, and Tet2 and downregulated that of Deptor in denervated muscle. In vitro experiments revealed that satellite cells derived from Opg knockout mice displayed a better differentiation ability than those acquired from wild-type littermates. Higher expression levels of Tet2 were also observed in satellite cells derived from Opg knockout mice, which provided a mechanistic basis for the protective effects of Opg knockout on muscle atrophy. Taken together, our findings uncover the novel role of Opg in muscle atrophy process and extend the current understanding in the OPG/RANKL/RANK signaling axis.
2023-05-01 | GSE220152 | GEO
Project description:The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation, but little is known concerning atrophy and its underlying mechanisms in denervated muscle to date. Here, we reported that activated NOD-like receptor protein 3 (NLRP3) inflammasome with pyroptotic cell death occurred in denervated gastrocnemius in the mouse model of sciatic denervation. This damage causes interleukin 1 beta (IL-1β) release，facilitating the ubiquitin proteasome system (UPS) activation, which was responsible for muscle proteolysis. Conversely, genetic knock-out of muscular NLRP3 inhibited the pyroptosis-associated protein expression and ameliorate muscle atrophy significantly. Meanwhile, co-treatment with shRNA-NLRP3, also remarkably attenuated NLRP3 inflammasome activator (NIA)-induced C2C12 myotube pyroptosis and atrophy. Interestingly, we also observed a correlation between NLRP3 inflammasome activation and muscular apoptosis possibly via caspase 1 mediation after denervation. This work for the first time elucidates on the roles and mechanisms of NLRP3 inflammasome in skeletal muscle atrophy during denervation and suggests the potential contribution to the pathogenesis of neuromuscular diseases.
2022-12-29 | GSE201133 | GEO
Project description:Samples of denervated GA muscle were compared to contralateral controls to determine transcriptional changes associated with skeletal muscle denervation.
2020-01-06 | GSE62812 | GEO
Project description:The right legs of 3 months old CD1 mice were denervated by unilaterally cutting the sciatic nerve at the level of trochanter, resulting in a permanent denervation of the lower hindleg. At the indicated times, animals were killed by cervical dislocation and tibialis anterior (TA) muscles were dissected out and frozen in liquid nitrogen. The expression analysis was carried out at five time points, namely just after denervation (time 0) and 1, 3, 7 and 14 days after nerve interruption. The contralateral, left TA muscle from the same individual served as innervated control. We reversed labeling of denervated and contralateral samples in each experiment, thus carrying out two separate hybridizations for each time point. Keywords = mouse Keywords = fast-twitch muscle Keywords = denervation Keywords = atrophy Keywords: time-course
2005-09-21 | GSE1893 | GEO
Project description:To identify novel atrophy-related genes, which are controlled by BMP signaling, we performed gene expression profiling on innervated and 14 days denervated muscles of Smad4 knockout and control mice, focusing on genes that were differentially upregulated in denervated Smad4-/- muscles compared to controls. Among the different genes our attention was attracted by a gene that encodes for a novel f-box protein (Fbxo30) belonging to the SCF complex family of the ubiquitin ligases. Cell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate Myostatin lead to important muscle growth in animals and humans. However, the signals and pathways responsible for this hypertrophy remain largely unknown. Here we find that BMP signaling, acting through Smad1/5/8, is the fundamental hypertrophic signal. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of Myostatin knockout and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 negatively regulates a novel gene (Fbxo30) that encodes an ubiquitin ligase, that is required for muscle loss. Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy. Gene expression profiling on innervated and 14 days denervated muscles of Smad4 knockout and control mice. Three independent experiments were performed for each experimental condition using different animals for each experiment.
2013-09-17 | E-GEOD-49826 | biostudies-arrayexpress
Project description:Current atlas of regulatory sequences controlling skeletal muscle atrophy are still incomplete and lack cell type resolution. We applied single-cell chromatin accessibility assays (snATAC) to normal and denervated skeletal muscle from mice. We integrated these snATAC datasets with our single-nucleus RNA-sequence dataset to reveal the status of open chromatin. Using these datasets, we delineated chromatin accessibility maps in both normal and atrophic muscles and identified cis-regulatory elements (CREs) in all type of cell in skeletal muscle that may regulating muscle protein metabolism, energy metabolism and transcription activities, thus, provided a rich resource for understanding gene regulatory programs in skeletal muscle and related disorders.
2023-09-06 | GSE217575 | GEO
Project description:Skeletal muscle exhibits remarkably plasticity under both physiological and pathological conditions. We used adult mice with sciatic denervation as model of muscle atrophy. SnRNA-seq was performed to generate single-nucleus transcriptome profiles of gastrocnemius from normal and denervation mice. Our results define the myonuclear transition, metabolic remodeling and gene regulation networks associated with muscle atrophy induced by denervation and illustrated the molecular basis of heterogeneity and plasticity of muscle cells in response to muscle atrophy, thus providing a resource for exploring molecular mechanisms leading to muscle atrophy
2021-11-02 | GSE183802 | GEO