Glucose Metabolism Drives Histone Acetylation Landscape Transitions that Dictate Muscle Stem Cell Function

Yucel, Nora; Wang, Yu Xin; Mai, Thach; Porpiglia, Ermelinda; Lund, Peder J.; Markov, Glenn J.; Garcia, Benjamin A.; Bendall, Sean C.; Angelo, Michael; Blau, Helen M.

doi:10.1016/j.celrep.2019.05.092

Cited by 124 publications

(126 citation statements)

References 75 publications

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“…Metabolism has been shown to play a crucial role in the function of many tissue resident stem cells 17 . Specifically in the context of MuSCs, recent work has shown that MuSCs display an increase in glycolytic metabolism during activation and this is important for muscle regeneration 2,3 . We similarly observed that rates of glycolysis increase during activation ( Figures 2C and 2E).…”

Section: Discussionmentioning

confidence: 99%

“…This regenerative ability largely depends on the function of its tissue resident muscle stem cells (MuSCs), also known as satellite cells. Under homeostatic conditions, MuSCs exist in a quiescent state characterized by small size, low transcription, and low metabolic activity [1][2][3][4][5] When muscle is injured, signals from the damaged tissue environment induce MuSCs to activate, i.e. to exit the quiescent state, enter the cell cycle, and proliferate.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, deficiency in SIRT1 activity leads to defects in autophagic flux needed to meet the bioenergetic demands of MuSC activation, and consequently delays MuSC activation and muscle regeneration 3,5 . Furthermore, loss of function of pyruvate dehydrogenase kinase (PDK) 2 and PDK4 in MuSCs contributes to dysregulation of glucose metabolism during activation and is associated with impaired muscle regeneration 2 . While this work ha shown the important role of metabolism in MuSC activation, there have been no systematic investigations of metabolic substrate utilization by MuSCs.…”

Section: Introductionmentioning

confidence: 99%

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Metabolism of glucose and glutamine is critical for skeletal muscle stem cell activation

Rodgers

Ahsan

Raval

et al. 2020

Preprint

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Injury to muscle tissue induces the resident, quiescent, skeletal muscle stem cells (MuSCs) to activate - to exit quiescence and enter the cell cycle. Previous work has shown that MuSC activation is associated with significant metabolic changes, however the substrates that MuSCs consume to support activation are poorly understood. Here, we show that MuSCs generate the majority of their energy through mitochondrial respiration, and that oxidative phosphorylation is required for MuSC activation. Furthermore, we have found that while glucose, glutamine, and fatty acids all significantly, and roughly equally, contribute to ATP production in MuSCs during activation, they do not have equal functional role in the dynamics of MuSC activation. Pharmacologic suppression of glycolysis, using 2-deoxy-D-glucose, or glutaminolysis, using BPTES, significantly impairs MuSC cell cycle entry. However, etomoxir-mediated inhibition of mitochondrial fatty acid transport has minimal effect on MuSC cell cycle progression. Our findings suggest that apart from their roles in fueling ATP production by the mitochondria, glucose and glutamine may generate metabolic intermediates needed for MuSC activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolism of glucose and glutamine is critical for skeletal muscle stem cell activation

Rodgers

Ahsan

Raval

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Defective MuSC mitochondrial function results in impaired tissue regeneration 29 and MuSCs with greater mitochondrial content and oxidative phosphorylation are associated with increased capability of initiating myogenic colonies 22 . Interestingly, across tissue-specific stem cells there is increasing evidence for a link between stem cell metabolism and epigenetics 25,26,33,47 . Quiescent HSCs rely on glycolysis during selfrenewal state.…”

Section: Discussionmentioning

confidence: 99%

“…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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Lactate promotes myogenesis via activating H3K9 lactylation‐dependent up‐regulation of Neu2 expression

Dai,

Wu,

Liu

et al. 2023

J cachexia sarcopenia muscle

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BackgroundLactate, a glycolytic metabolite mainly produced in muscles, has been suggested to regulate myoblast differentiation, although the underlying mechanism remains elusive. Recently, lactate‐mediated histone lactylation is identified as a novel epigenetic modification that promotes gene transcription.MethodsWe used mouse C2C12 cell line and 2‐month‐old male mice as in vitro and in vivo models, respectively. These models were treated with lactate to explore the biological function and latent mechanism of lactate‐derived histone lactylation on myogenic differentiation by quantitative real‐time PCR, western blotting, immunofluorescence staining, chromatin immunoprecipitation, cleavage under targets and tagmentation assay and RNA sequencing.ResultsUsing immunofluorescence staining and western blotting, we proposed that lactylation might occur in the histones. Inhibition of lactate production or intake both impaired myoblast differentiation, accompanied by diminished lactylation in the histones. Using lactylation site‐specific antibodies, we demonstrated that lactate preferentially increased H3K9 lactylation (H3K9la) during myoblast differentiation (CT VS 5, 10, 15, 20, 25 mM lactate treatment, P = 0.0012, P = 0.0007, and the rest of all P < 0.0001). Notably, inhibiting H3K9la using P300 antagonist could block lactate‐induced myogenesis. Through combined omics analysis using cleavage under targets and tagmentation assay and RNA sequencing, we further identified Neu2 as a potential target gene of H3K9la. IGV software analysis (P = 0.0013) and chromatin immunoprecipitation‐qPCR assay (H3K9la %Input, LA group = 9.0076, control group = 2.7184, IgG = 0.3209) confirmed that H3K9la is enriched in the promoter region of Neu2. Moreover, siRNAs or inhibitors against Neu2 both abrogated myoblast differentiation despite lactate treatment, suggesting that Neu2 is required for lactate‐mediated myoblast differentiation.ConclusionsOur findings provide novel understanding of histone lysine lactylation, suggesting its role in myogenesis, and as potential therapeutic targets for muscle diseases.

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Glucose Metabolism Drives Histone Acetylation Landscape Transitions that Dictate Muscle Stem Cell Function

Cited by 124 publications

References 75 publications

Metabolism of glucose and glutamine is critical for skeletal muscle stem cell activation

Metabolism of glucose and glutamine is critical for skeletal muscle stem cell activation

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

Lactate promotes myogenesis via activating H3K9 lactylation‐dependent up‐regulation of Neu2 expression

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