Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in locomotor and respiratory muscles during experimental sepsis in mice

Morel, J.; Palao, Jean-Charles; Castells, J.; Desgeorges, Marine Maud; Busso, Thierry; Molliex, Serge; Jahnke, Vanessa E.; Carmine, Peggy Del; Gondin, Julien; Arnould, David; Durieux, Anne-Cécile; Freyssenet, Damien

doi:10.1038/s41598-017-11440-5

Cited by 22 publications

(31 citation statements)

References 66 publications

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“…Autophagy can be triggered through multiple interconnected pathways, such as the MAPK, PI3K-AKT-mTOR and ATP-AMPK-mTOR signaling pathways 32 , 33 . MAPK signaling pathways have a vital role in interfering with autophagy in several types of cells 34 .…”

Section: Discussionmentioning

confidence: 99%

Zearalenone altered the cytoskeletal structure via ER stress- autophagy- oxidative stress pathway in mouse TM4 Sertoli cells

Zheng

Wang

et al. 2018

Sci Rep

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The aim of this study was to investigate the molecular mechanisms of the destruction of cytoskeletal structure by Zearalenone (ZEA) in mouse-derived TM4 cells. In order to investigate the role of autophagy, oxidative stress and endoplasmic reticulum(ER) stress in the process of destruction of cytoskeletal structure, the effects of ZEA on the cell viability, cytoskeletal structure, autophagy, oxidative stress, ER stress, MAPK and PI3K- AKT- mTOR signaling pathways were studied. The data demonstrated that ZEA damaged the cytoskeletal structure through the induction of autophagy that leads to the alteration of cytoskeletal structure via elevated oxidative stress. Our results further showed that the autophagy was stimulated by ZEA through PI3K-AKT-mTOR and MAPK signaling pathways in TM4 cells. In addition, ZEA also induced the ER stress which was involved in the induction of the autophagy through inhibiting the ERK signal pathway to suppress the phosphorylation of mTOR. ER stress was involved in the damage of cytoskeletal structure through induction of autophagy by producing ROS. Taken together, this study revealed that ZEA altered the cytoskeletal structure via oxidative stress - autophagy- ER stress pathway in mouse TM4 Sertoli cells.

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Section: Discussionmentioning

confidence: 99%

Zearalenone altered the cytoskeletal structure via ER stress- autophagy- oxidative stress pathway in mouse TM4 Sertoli cells

Zheng

Wang

et al. 2018

Sci Rep

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“…The current study indicates that in the CLP‐induced model of sepsis in mice, DIA fiber atrophy is transient, lasting 24 h after sepsis is initiated, and TA fiber atrophy is sustained, lasting 96 h. These results suggest that the DIA is less sensitive than the TA to the inhibitory effects of CLP‐induced sepsis on fiber size and are in accordance with the work of Prentice et al (), who concluded that the ventilatory muscles are relatively spared from the damaging effects of sepsis in comparison to the limb muscles. Several other studies using the CLP model of sepsis in rats and mice give added weight to this view in that they demonstrate that oxidative stress levels, protein breakdown, and fiber atrophy are significantly lower in the DIA than in limb muscles (Tiao et al, ; Morel et al, ; Stana et al, ; Talarmin et al, ). The mechanisms involved in the relative resistance of the DIA to sepsis‐induced fiber atrophy in our model remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The rationale for comparing the diaphragm to a limb muscle was to determine whether myofibrillar proteins in the ventilatory muscles are differentially less sensitive to the adverse effects of sepsis as compared to limb muscles due to their more sustained activity level. We hypothesize, based on previous studies in septic humans and experimental animals, that myofibrillar protein levels in the ventilatory muscles are relatively spared from the inhibitory effects of sepsis in comparison to the limb muscles (Tiao et al, 1997;Morel et al, 2017;Stana et al, 2017;Talarmin et al, 2017).…”

Section: Introductionmentioning

confidence: 97%

Differential regulation of myofibrillar proteins in skeletal muscles of septic mice

et al. 2019

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Sepsis elicits skeletal muscle atrophy as a result of decreased total protein synthesis and/or increased total protein degradation. It is unknown how and whether sepsis differentially affects the expression of specific myofibrillar proteins in respiratory and limb muscles. In this study, we measured the effects of sepsis myofibrillar mRNAs and their corresponding protein levels in the diaphragm (DIA) and tibialis anterior (TA) muscles in a murine cecal ligation and perforation (CLP) model of sepsis. Male mice (C57/BL6j) underwent CLP‐induced sepsis. Sham‐operated mice were subjected to the same surgical procedures, except for CLP. Mice were euthanized 24, 48, or 96 h postsurgery. Transcript and protein levels of autophagy‐related genes, ubiquitin E3 ligases, and several myofibrillar genes were quantified. Sepsis elicited transient fiber atrophy in the DIA and prolonged atrophy in the TA. Atrophy was coincident with increased autophagy and ubiquitin E3 ligase expression. Myosin heavy chain isoforms decreased at 24 h in the DIA and across the time‐course in the TA, myosin light chain isoforms decreased across the time‐course in both muscles, and troponins T and C as well as tropomyosin decreased after 24 and 48 h in both the DIA and TA. α‐Actin and troponin I were unaffected by sepsis. Sepsis‐induced decreases in myofibrillar protein levels coincided with decreased mRNA expressions of these proteins, suggesting that transcriptional inhibition is involved. We hypothesize that sepsis‐induced muscle atrophy is mediated by decreased transcription and enhanced degradation of specific myofibrillar proteins, including myosin heavy and light chains, troponin C, troponin T, and tropomyosin.

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“…Studies [ 33 , 34 , 35 ] have shown that autophagy regulates the intracellular homeostatic mechanism that mediates protein and organelle degradation. Autophagy can be induced through multiple interconnected pathways, such as the MAPK, PI3K-AKT-mTOR, and ATP-AMPK-m TOR signaling pathways [ 36 , 37 ]. In our study, the immunofluorescence analyses show that as ZEA concentration increased, the LC3 accumulation in SCs significantly increased and the number of acidic vesicles increased ( Figure 3 C).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Autophagy and PI3K/AKT/m-TOR Signaling Pathway on the Cell-Cycle Arrest of Rats Primary Sertoli Cells Induced by Zearalenone

Wang

Zheng

Feng

et al. 2018

Toxins

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A high concentration of Zearalenone (ZEA) will perturb the differentiation of germ cells, and induce a death of germ cells, but the toxic mechanism and molecular mechanism remain unclear. The Sertoli cells (SCs) play an irreplaceable role in spermatogenesis. In order to explore the potential mechanism of ZEA male reproductive toxicity, we studied the effects of ZEA on cell proliferation, cell-cycle distribution, cell-cycle-related proteins and autophagy-related pathway the PI3K/Akt/mTOR signaling in primary cultured rats SCs, and the effects of autophagy and PI3K/AKT/m TOR signaling pathway on the SCs cell-cycle arrest induced by ZEA treated with the autophagy promoter RAPA, autophagy inhibitor CQ, and the PI3K inhibitor LY294002, respectively. The data revealed that ZEA could inhibit the proliferation of SCs by arresting the cell cycle in the G2/M phase and trigger the autophagy via inhibiting the PI3K/Akt/m TOR signaling pathway. Promoting or inhibiting the level of autophagy could either augment or reverse the arrest of cell cycle. And it was regulated by PI3K/Akt/m TOR signaling pathway. Taken together, this study provides evidence that autophagy and PI3K/Akt/m TOR signaling pathway are involved in regulating rats primary SCs cell-cycle arrest due to ZEA in vitro. To some extent, ZEA-induced autophagy plays a protective role in this process.

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Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in locomotor and respiratory muscles during experimental sepsis in mice

Cited by 22 publications

References 66 publications

Zearalenone altered the cytoskeletal structure via ER stress- autophagy- oxidative stress pathway in mouse TM4 Sertoli cells

Zearalenone altered the cytoskeletal structure via ER stress- autophagy- oxidative stress pathway in mouse TM4 Sertoli cells

Differential regulation of myofibrillar proteins in skeletal muscles of septic mice

The Effects of Autophagy and PI3K/AKT/m-TOR Signaling Pathway on the Cell-Cycle Arrest of Rats Primary Sertoli Cells Induced by Zearalenone

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