A Dach2-Hdac9-Myog-Gdf5 signaling system regulates regeneration of neuromuscular synapses
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Ana Grant
PROVIDER: E-GEOD-58669 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration.
2015-10-29 | GSE58669 | GEO
Project description:The myogenic regulatory factor MRF4 is expressed at high levels in myofibers of adult skeletal muscle, but its function is unknown. Here we show that knockdown of MRF4 in adult muscle causes hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and the widespread activation of genes involved in muscle contraction, excitation-contraction coupling and energy metabolism, many of which are known targets of MEF2 transcription factors. Genes regulated by MEF2 represent the top-ranking gene set enriched after Mrf4 RNAi, and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The role of MEF2 in mediating the effect of MRF4 knockdown is supported by the finding that Mrf4 RNAi-dependent increase in fiber size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofiber hypertrophy. The nuclear localization of the MEF2 co-repressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. The demonstration that fiber size in adult skeletal muscle is controlled by the MRF4-MEF2 axis opens new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia. Adult innervated and denervated rat soleus muscles were transfected with shRNA to Mrf4 (M1) or to LacZ as a control. Muscles were dissected and examined after 7 days. For each group/condition we selected three different muscles (biological replicas).
2016-07-15 | E-GEOD-67069 | biostudies-arrayexpress
Project description:To compare the microRNAs (miRNAs) expression profile in the innervated soleus muscle and L4-L6 DRG neuronsafter sciatic nerve entrapment with a non-constrictive silastic tube, subsequent surgical decompression, and denervation injury. The experimental soleus muscles and dorsal root ganglions (DRGs) from each experimental group (sham control, denervation, entrapment, and decompression) were analyzed with an Agilent® rat miRNA array to detect dysregulated miRNAs Three-condition experiment, DRGs and soleus muscles of the rats receiving sciatic nerve denervation 6 months, sciatic nerve entrapment 6 months, and sciatic nerve entrapment 6 months then decompression for 3 months v.s. soleus muscle (sham control), Biological replicates: 1 control replicates, 3 experiment replicates
2010-06-12 | E-GEOD-22181 | biostudies-arrayexpress
Project description:This study aimed to quantify the regulation of transcripts in the hairy skin of the back of adult rats in the condition of loss of sensory and autonomic (sympathetic) innervation (i.e., denervated). Denervated skin has reduced wound healing capacity, reduced proliferation of epidermal progenitor cells, and also expresses factors that regulate ingrowth of sensory and sympathetic axons from neighboring regions of innervated skin. It was expected that this quantification f transcript regulation would offer insight into the general and specific mechanisms that may contribute to these important biological processes. All animals were adult (200-250g) Sprague-Dawley female rats. Three conditions were examined. Groups were naive (n=6), 7-day denervated skin (n=5), and 14-day (n=5) denervated skin. Denervation preparations: Full-thickness incision along long-axis of the body 1cm to right of midline (to avoid injuring skin to be sampled). Incision was centered rostro-caudally on the T13 (thoracic 13) costo-vertebral angle so as to allow access to the T9-L2 (lumbar 2) cutaneous nerves. Skin was reflected to the left and the left T9, T10, L1, and L2 dorsal and lateral cutaneous nerves were isolated, ligated with 7-0 monofilament suture close to their exit from the body wall, and transected. Approximately 5mm of the distal portion of the nerve was resected. The T11 nerves were left unperturbed and were not isolated from the surrounding fascia. This generated two strips of skin that were devoid of sensory and autonomic innervation (those strips served by the T9 and T10 nerves, and by the L1 and L2 nerves). Between these denervated strips of skin was a strip of skin that retained the sensory and autonomic axons supplied by T11 nerves. The denervated zones were identified by mapping the cutaneous trunk muscle (CTM) reflex (see Petruska-JC et al. (2013) Journal of Comparative Neurology; Diamond-J et al., (1992) J Neuroscience), and the border marked with pen and remarked every few days. The samples were taken from the rostral (T9/10) denervated zone. Samples from naive animals (no denervation) were taken from the same region, using the dorsal cutaneous nerves as registration landmarks. Animals displayed no signs of overgrooming of the denervated skin. Because the CTM inserts onto the dermis of this region of skin, samples necessarily include both skin and underlying CTM (which is innervated from another source so was not denervated in the experiment).
2014-04-08 | E-GEOD-54356 | biostudies-arrayexpress
Project description:The functional state of denervated muscle is a critical factor in the ability to restore movement after injury- or disease-related paralysis. Here we used peripheral optogenetic stimulation in the mouse whisker system to investigate the time course of changes in nerve and muscle function following facial nerve transection. While most skeletal muscles atrophy after lower motor neuron denervation, optogenetic muscle stimulation of the paralyzed whisker pad revealed sustained increases in the sensitivity, velocity, and amplitude of whisker movements, and reduced fatigability, starting 48 h after denervation. Transcriptome profiling showed distinct regulation of multiple gene families in denervated whisker pad muscles compared to the atrophy-prone soleus, including prominent changes in ion channels and contractile fibers. Together, our results define the functional and transcriptomic landscape of muscle denervation supersensensitivty, and have implications for restoring movement after neuromuscular injury or disease.
2018-11-19 | GSE121590 | GEO
Project description:Analysis of denervation induced regulation of muscle mass at gene expression level. The hypothesis tested in the present study was that the presence of MuRF1 contributes to the extent of gene expression changes observed in specific sets of genes during a challenge leading to muscle atrophy. Results provide important information on the response of triceps surae muscle to sciatic nerve resection (denervation), such as specific structural, metabolic, and neuromuscular junction associated genes, that may be influenced by MuRF1 during atrophy. Total RNA obtained from isolated triceps surae muscle subjected to 3 or 14 days post-denervation compared to nonsurgically treated littermate control muscles.
2013-02-12 | E-GEOD-44205 | biostudies-arrayexpress
Project description:Skeletal muscle denervation is a characteristic feature of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and sarcopenia, leading to atrophy, loss of muscle strength, and poor patient outcomes. Myofibers are typically classified into slow oxidative and fast glycolytic types based on their contractile and metabolic properties. Neuromuscular diseases predominantly affect fast myofibers, while slow myofibers are relatively spared. However, the mechanisms underlying the heightened susceptibility of fast myofibers to disease and atrophy remain unclear. To investigate this, we analyzed the transcriptional profiles of innervated and denervated myonuclei. Our findings revealed that the fast muscle gene program and the transcription factor Maf are repressed during denervation. Notably, overexpression of Maf in the skeletal muscles of mice prevented loss of muscle mass and myofiber atrophy caused by denervation. Single-nucleus RNA sequencing and ATAC sequencing demonstrated that Maf overexpression reprogrammed denervated myonuclei by repressing atrophic gene programs and reactivating fast muscle gene expression. Similar repression of fast muscle genes and Maf was observed in muscles from mice and humans with ALS. Consistent with these findings, Maf overexpression in human skeletal muscle cells induced the expression of fast muscle genes while suppressing atrophic gene expression. Our findings highlight a key role for Maf in maintaining muscle mass and demonstrate that its repression contributes to the progression of neuromuscular diseases in both mice and humans. Modulating Maf activity could offer a promising therapeutic strategy to preserve skeletal muscle function during disease, aging, or injury.
2025-05-29 | GSE298184 | GEO
Project description:Skeletal muscle denervation is a characteristic feature of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and sarcopenia, leading to atrophy, loss of muscle strength, and poor patient outcomes. Myofibers are typically classified into slow oxidative and fast glycolytic types based on their contractile and metabolic properties. Neuromuscular diseases predominantly affect fast myofibers, while slow myofibers are relatively spared. However, the mechanisms underlying the heightened susceptibility of fast myofibers to disease and atrophy remain unclear. To investigate this, we analyzed the transcriptional profiles of innervated and denervated myonuclei. Our findings revealed that the fast muscle gene program and the transcription factor Maf are repressed during denervation. Notably, overexpression of Maf in the skeletal muscles of mice prevented loss of muscle mass and myofiber atrophy caused by denervation. Single-nucleus RNA sequencing and ATAC sequencing demonstrated that Maf overexpression reprogrammed denervated myonuclei by repressing atrophic gene programs and reactivating fast muscle gene expression. Similar repression of fast muscle genes and Maf was observed in muscles from mice and humans with ALS. Consistent with these findings, Maf overexpression in human skeletal muscle cells induced the expression of fast muscle genes while suppressing atrophic gene expression. Our findings highlight a key role for Maf in maintaining muscle mass and demonstrate that its repression contributes to the progression of neuromuscular diseases in both mice and humans. Modulating Maf activity could offer a promising therapeutic strategy to preserve skeletal muscle function during disease, aging, or injury.
2025-05-29 | GSE298187 | GEO
Project description:Background: Skeletal muscle crucially depends on motor innervation, and, when damaged, on the resident muscle stem cells (MuSCs). However, the role and function of MuSCs in the context of denervation remains poorly understood. Methods: Alterations of MuSCs and their myofiber niche after denervation were investigated in a surgery-based mouse model of unilateral sciatic nerve transection. FACS-isolated MuSCs were subjected to RNA-sequencing and mass spectrometry for the analysis of intrinsic changes after denervation and in vivo assays, such as Cardiotoxin-induced muscle injury or MuSC transplantation, were performed to assess MuSC functions after denervation. Bioinformatic and histological analyses were conducted to further examine MuSCs and their myofiber niche after denervation. Results: Muscle cross section analysis revealed a significant increase in Pax7 (p-value= 0.0441), Pax7/Ki67 (p-value= 0.0023), MyoD (p-value= 0.0016) and Myog (p-value= 0.0057) positive cells after denervation, illustrating a break of quiescence and commitment to the myogenic lineage. An Omics approach showed profound intrinsic alterations on the mRNA (2613 differentially expressed genes, p-value <0.05) and protein (1096 differentially abundant proteins, q-value <0.05) level of MuSCs 21 days after denervation. Skeletal muscle injury together with denervation surgery caused deregulated regeneration, indicated by the reduced number of proliferating MuSCs and sustained high levels of developmental myosin heavy chain (Sham: 1 % vs DEN: 40 % of all myofibers), at 21 days post-surgery. In a transplantation assay, MuSCs from a denervated host were still able to engraft and fuse to form new myofibers, irrespective of the innervation status of the recipient muscle. Analysis of myofibers revealed not only massive changes in the expression profile (10492 differentially expressed genes, p-value <0.05) after denervation, but it was also shown that secretion of Opn and Tgfb1 from denervated myofibers was increased 30-fold and 6000-fold, respectively. Bioinformatic analyses indicated strong upregulation of gene expression of the transcription factor Junb in MuSCs from denervated muscles (log2 fold change = 3.27). Of interest, Tgfb1 recombinant protein was able to induce Junb gene expression in vitro, demonstrating that myofiber-secreted ligands can induce gene expression changes in MuSCs, which might result in the phenotypes observed after denervation. Conclusion: Skeletal muscle denervation is altering myofiber secretion, causing MuSC activation and profound intrinsic changes, leading to reduced regenerative capacity. As MuSCs possess a remarkable regenerative potential, they might represent a promising target for novel treatment options for neuromuscular disorders and peripheral nerve injuries.
2024-02-27 | PXD036993 | Pride
Project description:Muscle denervation causes skeletal muscle atrophy. The goal of these studies was to determine the effects of denervation on skeletal muscle mRNA levels in C57BL/6 mice. For additional details see Ebert et al, Stress-Induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy. JBC epub. June 12, 2012. Left sciatic nerves of C57BL/6 mice were transected. Seven days later bilateral tibialis anterior muscles were harvested. mRNA levels in denervated muscles were normalized to levels in contralateral innervated muscles.
2012-09-15 | E-GEOD-39195 | biostudies-arrayexpress