Loss of Nucleoporin Nup210 Results in Muscle Repair Delays and Age-Associated Alterations in Skeletal Muscle Integrity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188803 | GEO | 2021/12/13
REPOSITORIES: GEO
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Project description:Nuclear pore complexes, the channels connecting the nucleus with the cytoplasm, are built by multiple copies of ∼30 proteins called nucleoporins. Recent evidence has exposed that nucleoporins can play cell type-specific functions. Despite novel discoveries into the cellular functions of nucleoporins, their role in the regulation of mammalian tissue physiology remains mostly unexplored because of a limited number of nucleoporin mouse models. Here we show that ablation of Nup210/Gp210, a nucleoporin previously identified to play a role in myoblast differentiation and Zebrafish muscle maturation, is dispensable for skeletal muscle formation and growth in mice. We found that although primary satellite cells from Nup210 knockout mice can differentiate, these animals show delayed muscle repair after injury. Moreover, Nup210 knockout mice display an increased percentage of centrally nucleated fibers and abnormal fiber type distribution as they age. Muscle function experiments also exposed that Nup210 is required for muscle endurance during voluntary running. Our findings indicate that in mammals, Nup210 is important for the maintenance of skeletal muscle integrity and for proper muscle function providing novel insights into the in vivo roles of nuclear pore complex components.
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Project description:Loss of Nucleoporin Nup210 Results in Muscle Repair Delays and Age-Associated Alterations in Skeletal Muscle Integrity
| PRJNA780417 | ENA
Project description:Previously, we identified the nucleoporin gp210/Nup210 as a critical regulator of muscle and neuronal differentiation, but how this nucleoporin exerts its function and whether it modulates nuclear pore complex (NPC) activity remain unknown. Here, we show that gp210/Nup210 mediates muscle cell differentiation in vitro via its conserved N-terminal domain that extends into the perinuclear space. Removal of the C-terminal domain, which partially mislocalizes gp210/Nup210 away from NPCs, efficiently rescues the differentiation defect caused by the knockdown of endogenous gp210/Nup210. Unexpectedly, a gp210/Nup210 mutant lacking the NPC-targeting transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. We demonstrate that the endoplasmic reticulum (ER) stress-specific caspase cascade is exacerbated during Nup210 depletion and that blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells. Our results suggest that the role of gp210/Nup210 in cell differentiation is mediated by its large luminal domain, which can act independently of NPC association and appears to play a pivotal role in the maintenance of nuclear envelope/ER homeostasis.
| S-EPMC4362455 | biostudies-literature
Project description:The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.
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Project description:The nuclear pore complex (NPC) machinery is emerging as an important determinant in the maintenance of genome integrity and sensitivity to DNA double-strand break (DSB)-inducing agents, such as ionising radiation (IR). In this study, using a high-throughput siRNA screen, we identified the central channel NPC protein Nup54, and concomitantly its molecular partners Nup62 and Nup58, as novel factors implicated in radiosensitivity. Nup54 depletion caused an increase in cell death by mitotic catastrophe after IR, and specifically enhanced both the duration of the G2 arrest and the radiosensitivity of cells that contained replicated DNA at the time of IR exposure. Nup54-depleted cells also exhibited increased formation of chromosome aberrations arisen from replicated DNA. Interestingly, we found that Nup54 is epistatic with the homologous recombination (HR) factor Rad51. Moreover, using specific DNA damage repair reporters, we observed a decreased HR repair activity upon Nup54 knockdown. In agreement with a role in HR repair, we also demonstrated a decreased formation of HR-linked DNA synthesis foci and sister chromatid exchanges after IR in cells depleted of Nup54. Our study reveals a novel role for Nup54 in the response to IR and the maintenance of HR-mediated genome integrity.
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Project description:Gastrocnemius muscle-Deletion of TECRL promotes skeletal muscle repair
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Project description:Nogo, also called RTN4, functions through three isoforms including Nogo-A, -B, and -C. Although Nogo-A is a well-known CNS inhibitor and the level of Nogo-A is increased in muscles of ALS patients, its role in the regulation of skeletal muscle homeostasis and regeneration is still vague. In this study, we analyzed various pathological muscle condition of human and mouse model, and discovered significant increase of Nogo-A and myogenic factors. To understand the role of Nogo in skeletal muscle, muscle transcripts from Nogo+/+ and Nogo-/- mouse were analyzed and observed intensified gene expression involved in adipocyte differentiation and lipid metabolism, and reduced gene expression related to muscle differentiation and structure organization suggesting muscle disorder from muscle replacement with fat deposition. Skeletal muscle structure from Nogo null mice displayed dystrophic phenotypes including impaired myofiber structure and immune cell infiltrations, and dysregulated homeostatic features such as higher level of MyoD, procaspase 3, CHOP, and AKT compared to wild-type muscle. Notexin-injured Nogo deficient muscle resulted higher level of immune cell infiltration but defective in IL-6 production, a well-known myokine from immune cells, and abnormally upregulated regenerative muscle fibers than normal muscle. Therefore we hypothesized that increased Nogo-A in pathological conditions may regulate muscle regeneration. Then differentiating C2C12 cells and induced myogenic stem cells(iMSC) showed upregulated Nogo-A and Myogenin, and Nogo-A silencing in C2C12 cells abrogated the capability to differentiate into myotubes. In conclusion, Nogo functions to maintain muscle homeostasis and integrity, and altered Nogo-A expression in pathological muscle condition mediates muscle regeneration. These understanding suggests Nogo-A as a novel differentiation target for the treatment of myopathies at clinical set.
2019-05-31 | GSE131955 | GEO
Project description:Healthy skeletal muscle can regenerate after ischaemic, mechanical, or toxin-induced injury, but ageing impairs that regeneration potential. This has been largely attributed to dysfunctional satellite cells and reduced myogenic capacity. Understanding which signalling pathways are associated with reduced myogenesis and impaired muscle regeneration can provide valuable information about the mechanisms driving muscle ageing and prompt the development of new therapies. To investigate this, we developed a high-throughput in vitro model to assess muscle regeneration in chemically injured C2C12 and human myotube-derived young and aged myoblast cultures. We observed a reduced regeneration capacity of aged cells, as indicated by an attenuated recovery towards preinjury myotube size and myogenic fusion index at the end of the regeneration period, in comparison with younger muscle cells that were fully recovered. RNA-sequencing data showed significant enrichment of KEGG signalling pathways, PI3K-Akt, and downregulation of GO processes associated with muscle development, differentiation, and contraction in aged but not in young muscle cells. Data presented here suggests that repair in response to in vitro injury is impaired in aged vs. young muscle cells. Our study establishes a framework that enables further understanding of the factors underlying impaired muscle regeneration in older age.
2023-07-05 | E-MTAB-12248 | biostudies-arrayexpress
Project description:After a muscle injury, a process comprising inflammation, repair, and regeneration must occur in a time-sensitive manner for skeletal muscle to be adequately repaired and regenerated. This complex process is assumed to be controlled by various myeloid cell types, including monocytes and macrophages, though the mechanism is not fully understood. Aryl hydrocarbon receptor nuclear translocator-like (Arntl or Bmal1) is a transcription factor that controls the circadian rhythm and has been implicated in regulating myeloid cell functions. In the present study, we generated myeloid cell-specific Arntl conditional knockout (cKO) mice to assess the role of Arntl expressed in myeloid cell populations during the repair process after muscle injury. Myeloid cell-specific Arntl deletion impaired muscle regeneration after cardiotoxin injection. Flow cytometric analyses revealed that, in cKO mice, the numbers of infiltrating neutrophils and Ly6Chi monocytes within the injured site were reduced on days 1 and 2, respectively, after muscle injury. Moreover, neutrophil migration and the numbers of circulating monocytes were significantly reduced in cKO mice, which suggests these effects may account, at least in part, for the impaired regeneration. These findings suggest that Arntl, expressed in the myeloid lineage regulates neutrophil and monocyte recruitment and is therefore required for skeletal muscle regeneration.
| S-EPMC10130093 | biostudies-literature
Project description:Skeletal muscle mass and function decline more precipitously after the age 75 y. To provide insights into biologically relevant mechanisms for preserving muscle mass and physical function in advanced age, a battery of physical function tests, muscle cross-sectional area by MRI and a vastus lateralis muscle biopsy were performed in 15 octogenarian world class track and field masters athletes (MA) and 14 non-athlete age- and sex-matched controls (NA). Muscle samples were analyzed using liquid-chromatography mass spectrometry to generate proteomics data, by histochemistry to identify respiratory compromised muscle fibers, and by quantitative real-time polymerase chain reaction to estimate mtDNA copy number. Physical function and muscle cross-sectional area were higher in MA than NA. Of nearly 6,000 proteins identified and quantified in muscle biopsy specimens, ~800 were differentially represented in MA versus NA. Most of the differentially represented proteins related to mitochondrial structure and function and were overrepresented in muscle of MA versus controls, including TCA cycle, respiratory electron transport capacity (ETC), cristae formation, sirtuins, and 8 mtDNA-encoded proteins. On the contrary, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage dependent anion channel. In conclusion, high physical function in advanced age is associated with preservation of mitochondrial health and function, with underrepresentation of proteins that process pre-RNA and determine splicing variants, and underrepresentation of nuclear pore proteins.
| MSV000086195 | MassIVE