Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes

Baraibar, Martín A.; Hyzewicz, Janek; Rogowska-Wrzesińska, Adelina; Bulteau, Anne‐Laure; Prip‐Buus, Carina; Butler-Browne, Gillian; Friguet, Bertrand

doi:10.18632/aging.101126

Cited by 44 publications

(48 citation statements)

References 53 publications

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“…Considering that senescence-associated aging affects cellular amino acid metabolism, this may provide an explanation for defective tryptophan catabolism by senescent MSCs. 47–52 It has also been demonstrated that IDO in senescent MSCs undergo proteasomal degradation, which could additionally account for defective kynurenine production and associated impaired immune suppression. 53 Consistent with our previous study, we also show here that IL-10 expression is increased in macrophages cocultured with MSCs.…”

Section: Discussionmentioning

confidence: 99%

Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFNγ priming

Chinnadurai

Rajan

et al. 2017

Blood Advances

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Industrial-scale expansion of mesenchymal stromal cells (MSCs) is often used in clinical trials, and the effect of replicative senescence on MSC functionality is of mechanistic interest. Senescent MSCs exhibit cell-cycle arrest, cellular hypertrophy, and express the senescent marker β-galactosidase. Although both fit and senescent MSCs display intact lung-homing properties in vivo, senescent MSCs acquire a significant defect in inhibiting T-cell proliferation and cytokine secretion in vitro. IFNγ does not upregulate HLA-DR on senescent MSCs, whereas its silencing did not reverse fit MSCs’ immunosuppressive properties. Secretome analysis of MSC and activated peripheral blood mononuclear cell coculture demonstrate that senescent MSCs are significantly defective in up (vascular endothelial growth factor [VEGF], granulocyte colony-stimulating factor [GCSF], CXCL10, CCL2) or down (IL-1ra, IFNγ, IL-2r, CCL4, tumor necrosis factor-α, IL-5) regulating cytokines/chemokines. Unlike indoleamine 2,3 dioxygenase (IDO), silencing of CXCL9, CXCL10, CXCL11, GCSF, CCL2, and exogenous addition of VEGF, fibroblast growth factor-basic do not modulate MSCs’ immunosuppressive properties. Kynurenine levels were downregulated in senescent MSC cocultures compared with fit MSC counterparts, and exogenous addition of kynurenine inhibits T-cell proliferation in the presence of senescent MSCs. IFNγ prelicensing activated several immunomodulatory genes including IDO in fit and senescent MSCs at comparable levels and significantly enhanced senescent MSCs’ immunosuppressive effect on T-cell proliferation. Our results define immune functional defects acquired by senescent MSCs, which are reversible by IFNγ prelicensing.

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Section: Discussionmentioning

confidence: 99%

Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFNγ priming

Chinnadurai

Rajan

et al. 2017

Blood Advances

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“…Several proteins were recently identified in a proteomic study demonstrating in WI‐38 human fibroblasts a strong interplay between replicative senescence, selenium, and selenoproteins, which are known to play a role in antioxidant defense and redox homeostasis . Of note, the restricted subsets of modified proteins in senescent fibroblasts and myoblasts are different, although an overlap of four proteins, involved in protein quality control, cellular morphology, and energy metabolism, was found for both cell types . In this paper, these findings are described and further discussed in view of the potential impact of oxidatively modified proteins on the altered metabolism of both senescent myoblasts and fibroblasts, with a specific focus on energy metabolism.…”

Section: Introductionmentioning

confidence: 84%

“…Immunodetection of carbonylated, HNE‐ and AGE‐ modified proteins was performed after 1‐DE and 2‐DE on young and senescent human WI‐38 fibroblasts and skeletal muscle satellite cells . Increased levels of these oxidative modifications were observed during replicative senescence in both cell types, encouraging the identification of the proteins targeted by these modifications and, hence, the potential mechanisms by which this accumulation of modified proteins could affect cellular functions.…”

Section: Protein Oxidative Modifications In Senescent Fibroblasts Andmentioning

confidence: 99%

“…Increasingly modified proteins with RMI (Relative Modification Index) ≥1.3 after the experimental procedures described in ref. [].…”

Section: Protein Oxidative Modifications In Senescent Fibroblasts Andmentioning

confidence: 99%

“…For example, ALDH4A1 and ALDH2 are respectively involved in acetaldehyde and glutamate semi‐aldehyde detoxification and their adduction with lipid peroxidation products could increase the load of reactive aldehyde in senescent fibroblasts. In addition, HSD17B, DLD, and NDUFS2, as component of NADH dehydrogenase, complex I of the respiratory chain, can influence the redox homeostasis through the dysregulation of the couple NADH/NAD + as observed for both myoblasts and fibroblasts ( Figure ) although in opposite directions. Indeed, changes of the NAD + /NADH ratio can modulate mitochondrial quantity and quality .…”

Section: Protein Oxidative Modifications In Senescent Fibroblasts Andmentioning

confidence: 99%

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Proteome Oxidative Modifications and Impairment of Specific Metabolic Pathways During Cellular Senescence and Aging

et al. 2019

Self Cite

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Accumulation of oxidatively modified proteins is a hallmark of organismal aging in vivo and of cellular replicative senescence in vitro. Failure of protein maintenance is a major contributor to the age‐associated accumulation of damaged proteins that is believed to participate to the age‐related decline in cellular function. In this context, quantitative proteomics approaches, including 2‐D gel electrophoresis (2‐DE)‐based methods, represent powerful tools for monitoring the extent of protein oxidative modifications at the proteome level and for identifying the targeted proteins, also referred as to the “oxi‐proteome.” Previous studies have identified proteins targeted by oxidative modifications during replicative senescence of human WI‐38 fibroblasts and myoblasts and have been shown to represent a restricted set within the total cellular proteome that fall in key functional categories, such as energy metabolism, protein quality control, and cellular morphology. To provide mechanistic support into the role of oxidized proteins in the development of the senescent phenotype, untargeted metabolomic profiling is also performed for young and senescent myoblasts and fibroblasts. Metabolomic profiling is indicative of energy metabolism impairment in both senescent myoblasts and fibroblasts, suggesting a link between oxidative protein modifications and the altered cellular metabolism associated with the senescent phenotype of human myoblasts and fibroblasts.

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Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype

Liang,

Pan,

Yin

et al. 2023

Advanced Science

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The essential branched‐chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs’ full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence‐associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation‐related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age‐related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age‐related and inflammatory diseases.

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Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes

Cited by 44 publications

References 53 publications

Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFNγ priming

Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFNγ priming

Proteome Oxidative Modifications and Impairment of Specific Metabolic Pathways During Cellular Senescence and Aging

Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype

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