Transcriptomic adaptations of human muscle in patients with polyarteritis nodosa and muscle denervation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE311567 | GEO | 2026/04/23
REPOSITORIES: GEO
Similar Datasets
Project description:Skeletal muscles undergo atrophy in response to denervation and neuromuscular diseases. Understanding the mechanisms by which denervation drives muscle atrophy is crucial for developing therapies against neurogenic muscle atrophy. Here, we identify muscle-secreted fibroblast growth factor 21 (FGF21) as a key inducer of atrophy following muscle denervation. In denervated skeletal muscles, Fgf21 is the most robustly upregulated member of the Fgf family and acts in an autocrine/paracrine manner to promote muscle atrophy. Silencing Fgf21 in muscle prevents denervation-induced muscle wasting by preserving neuromuscular junction (NMJ) innervation. Conversely, forced expression of FGF21 in muscle reduces NMJ innervation, leading to muscle atrophy. Mechanistically, TGFB1 released by denervated fibro-adipogenic progenitors (FAPs) upregulates Fgf21 through the JNK/c-Jun axis. The resulting increase in FGF21 protein reduces the cytoplasmic level of histone deacetylase 4 (HDAC4), culminating in muscle atrophy. HDAC4 knockdown abolishes the atrophy-resistant effects observed in Fgf21-deficient denervated muscles, resulting in muscle atrophy. Our findings reveal a novel role and heretofore unrecognized mechanism of FGF21 in skeletal muscle atrophy, suggesting that inhibiting muscular FGF21 could be a promising strategy for mitigating skeletal muscle atrophy.
2025-11-06 | GSE303861 | GEO
Project description:The molecular mechanisms underlying the opposing states of muscle atrophy (such as with disuse or in aging) and hypertrophy (such as with increased physical activity) are still not well-defined. Progress has been slowed by challenges in characterizing the niche heterogeneity of skeletal muscle (whereby myofibers are the most abundant) and in obtaining well-characterized samples. Here we describe: i) changes in muscle cell populations that are undergoing atrophy or hypertrophy, with complex, opposing cell transcriptional responses during each process; and ii) a remarkable remodeling of the neuromuscular junction (NMJ) domain, whereby we identify emerging new subpopulations of synaptic myonuclei (SynM) and terminal Schwann cells (tSCs) that are specifically adapted to each growth/atrophy condition. High-resolution 3D imaging and spatial transcriptomics reveal these structural and molecular adaptations at the tissue level. Critically, these changes also occur in the NMJ of both denervated and exercised human muscle. Our study lays the ground for identifying novel targets for medical, pharmacological and lifestyle interventions in aging and disease.
2026-04-23 | GSE294765 | GEO
Project description:The molecular mechanisms that govern muscle hypertrophy (as induced by increased physical activity) remain incompletely defined. Through RNA-seq of human muscle, we confirm observations from mice that extensive remodeling of the neuromuscular junction (NMJ) occurs in human muscle after exercise.
2026-04-23 | GSE312393 | GEO
Project description:This investigation leverages single-cell RNA sequencing (scRNA-Seq) to delineate the contributions of muscle-resident Schwann cells to neuromuscular junction (NMJ) remodeling in models of healthy, partially denervated, and completely denervated muscles. The study identifies several distinct Schwann cell subtypes, notably a novel terminal Schwann cell (tSC) subtype integral to the denervation-reinnervation cycle, distinguished by a transcriptomic signature indicative of cell migration and polarization. It also characterizes three myelin Schwann cell subtypes, which are notably enriched with genes associated with myelin production, in addition to mesenchymal differentiation and collagen synthesis. Importantly, SPP1 signaling emerges as a pivotal regulator of NMJ dynamics, promoting Schwann cell proliferation and muscle reinnervation across the studied nerve injury models. These findings advance our understanding of NMJ maintenance and regeneration and underscore the therapeutic potential of targeting specific molecular pathways to treat neuromuscular and neurodegenerative disorders.
2025-03-12 | GSE291457 | GEO
Project description:Innervation of skeletal muscle fibers plays a crucial role in the maintenance of muscle tone and normal functioning, but little is known to date about denervated muscle atrophy and its underlying mechanisms. To this end, we performed RNA sequencing of skeletal muscle from sciatic nerve-excised C57BL/6 and BALB/c mice to investigate the underlying mechanisms of denervated skeletal muscle atrophy.
2024-10-31 | GSE253469 | 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: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: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.
2013-02-12 | GSE44205 | GEO
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