10 results on '"Cussonneau L"'
Search Results
2. Concurrent BMP maintenance and TGF-β inhibition is a hallmark of bear resistance to muscle atrophy
- Author
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Cussonneau, L, Dubois, E, Arnemo, J, Bertile, F, Lefai, E, Combaret, L, INRAE, Université Clermont Auvergne, and Société Française de Myologie
- Subjects
[SDV]Life Sciences [q-bio] ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] - Abstract
International audience; Muscle atrophy arises from a multiplicity of physiological or pathological situations (e.g., aging, physical inactivity, diabetes, cancers …) and its consequences are very detrimental at whole-body level. Even though knowledge of the underlying mechanisms keeps growing, there is still no proven treatment to date. To address this major clinical challenge, we selected here an innovative approach that compares muscle adaptations between an original model of natural resistance to muscle atrophy, the hibernating brown bear (Ursus arctos), and a classical model of physical inactivity-induced atrophy, the unloaded mouse. Throughout the hibernation season, the brown bear remains continuously torpid up for 5-7 months, without normothermic interbout arousals, and thus dealing with fasting and prolonged physical inactivity. Remarkably, even facing with these two main atrophic inducers, the bear has the unique ability to withstand muscle loss. Using transcriptomic analysis by RNA sequencing, we identified 2693 differentially expressed genes between the active versus hibernating period in bear muscle. A general downregulation of genes involved in extracellular matrix structure organization was observed in the hibernating brown bear. We then decided to focus on TGF-β superfamily including i) the TGF-β signaling being a master regulator of the extracellular matrix organization, and as well involved in muscle mass loss and ii) the BMP signaling, recently discovered involved in muscle mass maintenance. During hibernation, gene expression of the TGF-β and BMP pathways components was overall downregulated and upregulated, respectively. On the contrary, an increased expression of TGF-β signaling genes and a decreased expression of BMP signaling genes was observed in mice muscles during physical inactivity. We have further substantiated this opposite regulation between atrophied muscles of the unloaded mouse and non-atrophied muscles of the hibernating bear at the protein level. Altogether, our data identified a balance between TGF-β and BMP signaling pathways as crucial for muscle mass maintenance during long-term physical inactivity. In addition to the TGF-β pathway, already targeted in a wide range of therapies, the BMP pathway therefore appears to be an additional potential therapeutic target to prevent muscle atrophy.
- Published
- 2021
3. Concurrent BMP signaling maintenance and TGF-β signaling inhibition is a hallmark of natural resistance to muscle atrophy
- Author
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Cussonneau, L, Boyer, B, Meugnier, E, Gauquelin-Koch, G, Arnemo, J, Lefai, E, Bertile, F, Combaret, L., and INRAE, Université Clermont Auvergne
- Subjects
[SDV]Life Sciences [q-bio] ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] - Abstract
National audience; Muscle atrophy arises from a multiplicity of physiological or pathological situations (e.g. diabetes, cancers, aging, physical inactivity…) and its consequences are very detrimental at whole-body level. Even though knowledge of the underlying mechanisms keeps growing, there is still no proven treatment to date. To address this major clinical challenge, we selected here an innovative approach that compares muscle adaptations between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of disuse-induced atrophy in mouse. Remarkably, the bear has the unique ability to withstand muscle loss during hibernation, being able to cope with main triggers of atrophy, physical inactivity and prolonged fasting. Using transcriptomic analysis by RNA sequencing, we identified 2693 differentially expressed genes between the active versus hibernating period in bear muscle. We focused on TGF-β and BMP signaling pathways that are respectively involved in muscle mass loss and maintenance. During hibernation, gene expression of the TGF-β and BMP pathways components was overall downregulated and upregulated, respectively. On the contrary, an increased expression of TGF-β signaling genes and a decreased expression of BMP signaling genes was observed in mice muscles during unloading. We have further substantiated this opposite regulation between atrophied muscles of the unloaded mouse and non-atrophied muscles of the hibernating bear at the protein level. Altogether, our data identified a balance between TGF-β and BMP signaling pathways as crucial for muscle mass maintenance during long-term physical inactivity. In addition to the TGF-β pathway, already targeted in a wide range of therapies, the BMP pathway therefore appears to be an additional potential therapeutic target to prevent muscle atrophy.
- Published
- 2021
4. Genetic reprogramming involving a shift from TGF- β to BMP signaling for muscle mass maintenance in hibernating brown bear
- Author
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Cussonneau, L, Boyer, B, Deval, C, Meugnier, E, Gueret, E, Dubois, E, Béchet, D, Polge, C, Taillandier, D, Arnemo, J, Bertile, F, Lefai, E, Combaret, L, and INRAE, Université Clermont Auvergne
- Subjects
[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] - Abstract
National audience
- Published
- 2020
5. The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
- Author
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Piecyk M, Triki M, Laval PA, Duret C, Fauvre J, Cussonneau L, Machon C, Guitton J, Rama N, Gibert B, Ichim G, Catez F, Bourdelais F, Durand S, Diaz JJ, Coste I, Renno T, Manié SN, Aznar N, Ansieau S, Ferraro-Peyret C, and Chaveroux C
- Subjects
- Humans, Cell Line, Tumor, Stress, Physiological drug effects, Cell Proliferation drug effects, Apoptosis drug effects, Autophagy drug effects, Organelle Biogenesis, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Colonic Neoplasms genetics, Ribosomes metabolism, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics
- Abstract
Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2024
- Full Text
- View/download PDF
6. Induction of ATF4-Regulated Atrogenes Is Uncoupled from Muscle Atrophy during Disuse in Halofuginone-Treated Mice and in Hibernating Brown Bears.
- Author
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Cussonneau L, Coudy-Gandilhon C, Deval C, Chaouki G, Djelloul-Mazouz M, Delorme Y, Hermet J, Gauquelin-Koch G, Polge C, Taillandier D, Averous J, Bruhat A, Jousse C, Papet I, Bertile F, Lefai E, Fafournoux P, Maurin AC, and Combaret L
- Subjects
- Animals, Mice, Muscle, Skeletal metabolism, Signal Transduction, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Hibernation, Activating Transcription Factor 4 genetics, Activating Transcription Factor 4 metabolism, Muscular Atrophy metabolism, Ursidae
- Abstract
Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during hindlimb suspension (HS)-induced muscle atrophy. Firstly, we reported that periodic activation of ATF4-regulated atrogenes ( Gadd45a , Cdkn1a , and Eif4ebp1 ) by halofuginone was not associated with muscle atrophy in healthy mice. Secondly, halofuginone-treated mice even showed reduced atrophy during HS, although the induction of the ATF4 pathway was identical to that in untreated HS mice. We further showed that halofuginone inhibited transforming growth factor-β (TGF-β) signalling, while promoting bone morphogenetic protein (BMP) signalling in healthy mice and slightly preserved protein synthesis during HS. Finally, ATF4-regulated atrogenes were also induced in the atrophy-resistant muscles of hibernating brown bears, in which we previously also reported concurrent TGF-β inhibition and BMP activation. Overall, we show that ATF4-induced atrogenes can be uncoupled from muscle atrophy. In addition, our data also indicate that halofuginone can control the TGF-β/BMP balance towards muscle mass maintenance. Whether halofuginone-induced BMP signalling can counteract the effect of ATF4-induced atrogenes needs to be further investigated and may open a new avenue to fight muscle atrophy. Finally, our study opens the way for further studies to identify well-tolerated chemical compounds in humans that are able to fine-tune the TGF-β/BMP balance and could be used to preserve muscle mass during catabolic situations.
- Published
- 2022
- Full Text
- View/download PDF
7. Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear.
- Author
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Cussonneau L, Boyer C, Brun C, Deval C, Loizon E, Meugnier E, Gueret E, Dubois E, Taillandier D, Polge C, Béchet D, Gauquelin-Koch G, Evans AL, Arnemo JM, Swenson JE, Blanc S, Simon C, Lefai E, Bertile F, and Combaret L
- Subjects
- Animals, Bone Morphogenetic Proteins genetics, Disease Models, Animal, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Hindlimb Suspension, Male, Mice, Mice, Inbred C57BL, Muscular Atrophy genetics, Muscular Atrophy pathology, Quadriceps Muscle pathology, RNA-Seq, Signal Transduction, Time Factors, Transcriptome, Transforming Growth Factor beta genetics, Ursidae genetics, Bone Morphogenetic Proteins metabolism, Hibernation, Muscular Atrophy metabolism, Quadriceps Muscle metabolism, Transforming Growth Factor beta metabolism, Ursidae metabolism
- Abstract
Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-β and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-β- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-β/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-β inhibiting therapies already targeted to prevent muscle atrophy.
- Published
- 2021
- Full Text
- View/download PDF
8. Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells.
- Author
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Piecyk M, Triki M, Laval PA, Dragic H, Cussonneau L, Fauvre J, Duret C, Aznar N, Renno T, Manié SN, Chaveroux C, and Ferraro-Peyret C
- Abstract
Genetic alterations in non-small cell lung cancers (NSCLC) stimulate the generation of energy and biomass to promote tumor development. However, the efficacy of the translation process is finely regulated by stress sensors, themselves often controlled by nutrient availability and chemotoxic agents. Yet, the crosstalk between therapeutic treatment and glucose availability on cell mass generation remains understudied. Herein, we investigated the impact of pemetrexed (PEM) treatment, a first-line agent for NSCLC, on protein synthesis, depending on high or low glucose availability. PEM treatment drastically repressed cell mass and translation when glucose was abundant. Surprisingly, inhibition of protein synthesis caused by low glucose levels was partially dampened upon co-treatment with PEM. Moreover, PEM counteracted the elevation of the endoplasmic reticulum stress (ERS) signal produced upon low glucose availability, providing a molecular explanation for the differential impact of the drug on translation according to glucose levels. Collectively, these data indicate that the ERS constitutes a molecular crosstalk between microenvironmental stressors, contributing to translation reprogramming and proteostasis plasticity.
- Published
- 2021
- Full Text
- View/download PDF
9. Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control.
- Author
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Peris-Moreno D, Cussonneau L, Combaret L, Polge C, and Taillandier D
- Subjects
- Animals, Humans, Signal Transduction, Muscular Atrophy enzymology, Muscular Atrophy physiopathology, Protein Biosynthesis, Ubiquitin metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies.
- Published
- 2021
- Full Text
- View/download PDF
10. Specific shifts in the endocannabinoid system in hibernating brown bears.
- Author
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Boyer C, Cussonneau L, Brun C, Deval C, Pais de Barros JP, Chanon S, Bernoud-Hubac N, Daira P, Evans AL, Arnemo JM, Swenson JE, Gauquelin-Koch G, Simon C, Blanc S, Combaret L, Bertile F, and Lefai E
- Abstract
In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear's peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.
- Published
- 2020
- Full Text
- View/download PDF
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