<scp>AMPK</scp>α1‐<scp>LDH</scp> pathway regulates muscle stem cell self‐renewal by controlling metabolic homeostasis

Théret, Marine; Gsaier, Linda; Schaffer, Bethany E.; Juban, Gaëtan; Larbi, Sabrina Ben; Weiss‐Gayet, Michèle; Bultot, Laurent; Collodet, Caterina; Foretz, Marc; Desplanches, Dominique; Sanz, Pascual; Zang, Zizhao; Yang, Lin; Vial, Guillaume; Viollet, Benoı̂t; Sakamoto, Kei; Brunet, Anne; Chazaud, Bénédicte; Mounier, Rémi

doi:10.15252/embj.201695273

Cited by 101 publications

(103 citation statements)

References 86 publications

(201 reference statements)

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“…One key question is then to what extent this metabolism change might be necessary 458 for erythroid cells to differentiate, and if it might drive cells into the differentiation 459 process, as it has been proposed for other cell types [4,[43][44][45]. Our finding regarding 460 erythroid cells also support this hypothesis.…”

supporting

confidence: 69%

“…We further dissected 43 OXPHOS mechanisms by analyzing cell respiration response to different respiratory 44 chains inhibitors. Finally, LDHA role in erythroid progenitors self-renewal was assayed 45 using known molecular inhibitors and the CRISPR/Cas9 knock-out technology. Then, 46 to investigate whether LDHA downregulation could be responsible for metabolic state 47 changes in erythroid progenitors, we measured MMP of self-renewing cells following 48 inhibition of LDHA activity.…”

mentioning

confidence: 99%

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Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

Angélique

Vallin

Romestaing

et al. 2019

Preprint

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Author summarySingle-cell based gene expression data from one of our previous publication pointed out significant variations of LDHA level, an important metabolism player, during erythroid differentiation. Deeper investigations highlighted that a metabolic switch occurred along differentiation of erythroid cells as previously emphasized in stem cell differentiation. More precisely our finding showed that self-renewing progenitor cells relied mostly upon a glycolytic, lactate-productive, metabolism and required LDHA activity, whereas differentiating cells, mainly involved the aerobic mitochondrial oxidative phosphorylation (OXPHOS). However our careful kinetic study demonstrated that these metabolic rearrangements were coming along with a particular temporary event, occurring within the first 24h of erythroid differentiation. The activity of glycolytic metabolism and OXPHOS rose jointly with ATP production at 12-24h of the differentiation process before lactate-productive glycolysis sharply fall down and energy needs decline. Finally, our results showed that the metabolic switch mediated through LDHA drop and OXPHOS upkeep might be necessary for erythroid differentiation. We also discuss the possibility that metabolism, gene expression and epigenetics could act together in a circular manner as a driving force for differentiation. Introduction 1Metabolism is a biological process mostly involved in energy consumption, production 2 and distribution, which is essential for cell functions and survival.3 An emerging theme is the possible causal involvement of metabolic changes during a 4 differentiation process. In particular, glycolysis was shown to be characteristic of 5 self-renewing stem cells and of different types of progenitors, such as neuronal and 6 hematopoietic progenitor cells [1,2]. It has been demonstrated that stem cells tend to 7 switch from glycolytic metabolism toward mitochondrial oxidative phosphorylation 8 (OXPHOS) while they differentiate [3][4][5]. Accordingly, it was suggested that a balance 9 between glycolysis and OXPHOS metabolism could somehow guide the choice between 10 self-renewal and differentiation in stem cells fate [6]. It has also been demonstrated that 11 preventing the shutting down of the glycolytic pathway was detrimental for neuronal 12 differentiation [4]. Otherwise, regarding somatic cells reprogramming into induced 13 pluripotent stem cells, it has been reported that pluripotency induction required the 14 concomitant upregulation of glycolytic metabolism and downregulation of OXPHOS [7]. 15 Regarding erythroid differentiation, progenitors depend on glycolysis and present a 16 Warburg-like profile as they display a high proliferation rate and produce an abundant 17 amount of lactate [8]. However, few is known about glucose metabolism behavior during 18 erythroid differentiation, when compared to erythroid progenitors self-renewal. Mature 19 mammals erythrocytes were shown to rely upon lactate dehydrogenase to fulfill their 20 functions, depending therefore upon the glycolytic p...

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supporting

confidence: 69%

mentioning

confidence: 99%

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

Angélique

Vallin

Romestaing

et al. 2019

Preprint

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“…Overall, numerous studies have identified a positive correlation between MuSC oxidative capacity and several aspects of MuSC function including cell number and muscle regenerative activity [22][23][24] . Several recent reports have delineated mechanisms that connect key tricarboxylic acid (TCA) cycle intermediates with transcriptional and epigenetic changes important for the function of MuSCs in muscle regeneration [25][26][27][28][29] . Indeed, cellular metabolism has been linked to quiescence, self-renewal, and differentiation function in other tissue-specific stem cell systems as well [30][31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

PDH Mediated Mitochondrial Respiration Controls the Speed of Muscle Stem Cell Activation in Muscle Repair and Aging

Raval

Cheng

Guardino

et al. 2020

Preprint

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Decline in the skeletal muscle stem cell (MuSC) function is a major contributor to ageassociated impairments in muscle regeneration and function. The ability of MuSCs to activate (i.e. exit quiescence, enter the cell cycle, and divide) following injury is a critical step that initiates muscle regeneration. However, the mechanisms that regulate MuSC activation function are poorly understood. Here, we show that the activation function, specifically the speed by which cells progress through G0-G1, declines tremendously with age in mouse MuSCs. Using a number of in vivo models and ex vivo assays of MuSC activation and muscle regenerative functions, live cell metabolic flux analyses, and metabolomics we present data indicating that changes in MuSC mitochondrial flux underlie age-associated changes in MuSC activation. We show that, in the course of MuSC activation, there is a profound,16-fold, increase in ATP production rates, which is fueled largely by increases in pyruvate flux into mitochondria. We found that MuSCs from aged mice display progressive defects in the ability to increase mitochondrial flux during activation and that this correlates with higher levels of phosphorylated, inactivated, pyruvate dehydrogenase (PDH). Importantly, we demonstrate that pharmacologic and physiologic methods to induce dephosphorylation and activation of PDH in MuSCs are sufficient to rescue the activation and muscle regenerative functions of MuSCs in aged mice. Collectively the data presented show that MuSC mitochondrial function is a central regulator of MuSC activation and muscle regenerative functions. Moreover, our results suggest that approaches to increase MuSC pyruvate oxidation may have therapeutic potential to promote muscle repair and regeneration.

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“…On top of this, the novel capacity of cancer cells to adopt progenitor phenotype with metabolic reprogramming attracts substantial attention of researchers . In human cancers including HCC, the glycolytic signature of cancer stem cells have been portrayed in previous studies . Being a key regulator of hepatocyte differentiation, whether GATA6 is also responsible for rewiring cell metabolism in HCC still awaits investigation.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 In human cancers including HCC, the glycolytic signature of cancer stem cells have been portrayed in previous studies. 18,19 Being a key regulator of hepatocyte differentiation, whether GATA6 is also responsible for rewiring cell metabolism in HCC still awaits investigation. In this study, we carried out an indepth interrogation of the functional significance of GATA6 in HCC with reference to tumorigenicity, self-renewal, metastatic potential and metabolic phenotype.…”

Section: Introductionmentioning

confidence: 99%

Deregulated GATA6 modulates stem cell‐like properties and metabolic phenotype in hepatocellular carcinoma

Tan

Leung

Chan

et al. 2019

Intl Journal of Cancer

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Accumulating evidence illustrates the significance of cell plasticity in the molecular biology of liver cancer. Reprogramming of mature parenchymal cells to a less differentiated state by key molecular targets contributes to the pathogenesis of hepatocellular carcinoma (HCC). Hereby, we investigated the role of GATA6, a transcription factor implicated in hepatocyte lineage specification, in HCC. Our results demonstrated a lower expression of GATA6 in HCC tissues compared to the corresponding nontumoral liver tissues. Moreover, GATA6 underexpression, as observed in about 50% cases in our clinical cohort, was associated with a poorer degree of tumor cell differentiation and worse disease‐free survival outcome. In vitro, silencing of GATA6 in HCC cells augmented cell migration and invasion abilities of HCC cells by activating epithelial–mesenchymal transition. Self‐renewal was also enhanced in vitro. Consistently, in vivo tumorigenicity and self‐renewal was promoted upon GATA6 knockdown. Notably, suppression of GATA6 converts HCC cells to a metabolic phenotype recapitulating stem‐cell state. Expression of glycolytic markers was elevated in GATA6‐knockdown clones accompanied by increased glucose uptake; while overexpression of GATA6 resulted in opposite effects. Further to this, we identified that GATA6 bound to the promoter region of PKM gene and regulated PKM2 transcription. Taken together, downregulation of GATA6 directs HCC cells to glycolytic metabolism and fosters tumorigenicity, self‐renewal and metastasis. GATA6 is a transcriptional regulator and a genetic switch that converts the phenotypic reprogramming of HCC cells. It is a potential prognostic biomarker and therapeutic target for liver cancer.

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AMPKα1‐LDH pathway regulates muscle stem cell self‐renewal by controlling metabolic homeostasis

Cited by 101 publications

References 86 publications

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

Erythroid differentiation displays a peak of energy consumption concomitant with glycolytic metabolism rearrangements

PDH Mediated Mitochondrial Respiration Controls the Speed of Muscle Stem Cell Activation in Muscle Repair and Aging

Deregulated GATA6 modulates stem cell‐like properties and metabolic phenotype in hepatocellular carcinoma

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