Muscle Stem Cell Response to Perturbations of the Neuromuscular Junction Are Attenuated With Aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA698820 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13610659.fastq.gz | Fastqsanger.gz | |||
| SRR13610660.fastq.gz | Fastqsanger.gz | |||
| SRR13610661.fastq.gz | Fastqsanger.gz | |||
| SRR13610662.fastq.gz | Fastqsanger.gz | |||
| SRR13610663.fastq.gz | Fastqsanger.gz |
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Project description:During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function, which is often associated with denervation and a loss of muscle stem cells (MuSCs). A relationship between MuSCs and innervation has not been established however. Herein, we administered neuromuscular trauma to a MuSC lineage tracing model and observed a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ). In aging and in a model of neuromuscular degeneration (Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ and partially restored MuSC ability to engraft into NMJ proximal positions. Using single cell RNA-sequencing of MuSCs, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury. These data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.
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Project description:Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.
2018-08-21 | GSE118825 | GEO
Project description:During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs); however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout - Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.
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Project description:Muscle fibroadipogenic progenitor (FAP) cells, which are muscular mesenchymal cells that originate from lateral plate mesoderm have been proposed to act as a critical regulator for adult muscle homeostasis1–7, including the maturation and proper functioning of the neuromuscular junction (NMJ)3, Prx-Bap1 paper. However, the mechanism and intercellular crosstalk by which FAPs regulate the stability and functionality of neuromuscular system remains unknown. Here we show that FAPs not only locally but also systemically regulate the neuromuscular system through the secretion of a serine-type endopeptidase Granzyme E which may imply the previously unidentified endocrine function of FAPs. Local transplantation of wild-type FAPs into the neuromuscular disease model (Prrx1Cre;Bap1f/f, hereafter, cKO) can readily prevent neuromuscular defects, including degeneration of the neuromuscular junction and loss of motor neurons. These effects are found not only in transplanted hindlimb muscles but also in the contralateral hindlimb and even forelimb muscles. Notably, subcutaneous administration of microparticles encapsulating FAP-conditioned media into cKO mice was sufficient to restore normal neuromuscular functions. By analyzing the transcriptomic and secretomic profiles of FAPs, we identified a novel protein, Granzyme E, which is specifically expressed in and secreted by FAPs, and which indispensably regulates the structure and function of NMJ and motor neuron survival. Our study has defined a unique mechanism of Granzyme E-dependent, systemic control of the neuromuscular system by FAPs, which would provide a comprehensive understanding on the neuromuscular systems and their crosstalk with non-neuronal cells. These findings may provide a therapeutic benefit to treat NMJ-related diseases.
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Project description:Aging is associated with delayed skeletal muscle repair and regeneration. Loss of innervation occurs after degenerative muscle injury, however, the extent of denervation, whether the kinetics of reinnervation changes with aging, and the cellular consequences of neuromuscular junction (NMJ) disruption in adult and aged muscle have not been explored. Here we show after degenerative muscle injury progressive denervation and delayed reinnervation in aged compared to adult muscle. Using confocal microscopy and 3-D image rendering we found a relationship between innervation and myofiber size in aged regenerating muscle. Although timely inhibition of pro-inflammatory Ccr2 activity after degenerative muscle injury improved aged regenerated myofiber size, this was not associated with an increase in reinnervation. In contrast, single cell RNA sequencing (scRNASeq) analysis revealed denervation triggers an inflammatory response in target muscles regardless of age; however, pro-inflammatory signaling predominated in aged macrophages and fibroadipogenic progenitors (FAPs) compared to a pro-regenerative response in adult cells. Thus, denervation and delayed reinnervation of NMJs after injury is a feature of persistent pro-inflammatory signals associated with delayed repair and regeneration of aged muscle.
2022-06-05 | GSE205395 | GEO
Project description:Understanding neuromuscular junction (NMJ) repair mechanisms is essential for addressing degenerative neuromuscular conditions. Here, we focus on the role of muscle-resident Schwann cells in NMJ reinnervation. Using an accepted model of progressive NMJ degeneration, Sod1-/- mice, we identified a clear NMJ ‘regenerative window’ that allowed us to define cellular and molecular regulators of synapse remodeling and muscle fiber reinnervation. High-resolution imaging and single-cell RNA sequencing provide a detailed analysis of Schwann cell number, morphology, and transcriptome revealing multiple subtypes, including a previously unrecognized terminal Schwann cell (tSC) population expressing a synapse promoting signature. We also discovered a novel SPP1-driven cellular interaction between myelin Schwann cells and tSCs and show that it promotes tSC proliferation and reinnervation following nerve injury in wild type mice. Our findings offer important insights into molecular regulators critical in NMJ reinnervation that are mediated through tSCs to maintain NMJ function.
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Project description:The neuromuscular junction (NMJ) is a specialized tripartite synapse composed of the motor axon terminal, covered by perisynaptic Schwann cells (PSCs), and the muscle fibre, separated by a basal lamina. It is exposed to different kind of injures such as mechanical traumas, pathogens including neurotoxins, and neuromuscular diseases such as amyotrophic lateral sclerosis and immune-mediated disorders, and has retained throughout vertebrate evolution an intrinsic ability for repair and regeneration, at variance from central synapses1. Following peripheral nerve injury, an intense but poorly defined crosstalk takes place at the NMJ among its components, functional to nerve terminal regeneration. To identify crucial factors released by PSCs and the muscle to induce nerve regrowth, we performed a transcriptome analysis of the NMJ at different time points after injection of -latrotoxin, a presynaptic neurotoxin isolated from the venom of the black widow spider. This toxin is a simple and controlled method to induce an acute, localized and reversible nerve terminal degeneration not blurred by inflammation, and can help to identify molecules involved in the intra- and inter-cellular signalling governing NMJ regeneration.
2017-05-30 | E-MTAB-5730 | biostudies-arrayexpress
Project description:Fibroadipogenic Progenitor Regulates Neuromuscular Junction by Secreting Novel Protein Granzyme E
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