Muscle-specific overexpression of NCOAT<sup>GK</sup>, splice variant of <i>O</i>-GlcNAcase, induces skeletal muscle atrophy

Huang, Ping; Ho, Shiuh‐Rong; Wang, Kai; Roessler, Bryan C.; Zhang, Fengxue; Hu, Yong; Bowe, Damon B.; Kudlow, Jeffrey E.; Paterson, Andrew J.

doi:10.1152/ajpcell.00124.2010

Cited by 22 publications

(18 citation statements)

References 57 publications

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“…This excessive and mostly durable O‐GlcNAcylation on some proteins may modify their function and stability and promote the activation of muscle wasting process. Furthermore, in support of a role of OGA decrease in GC‐induced atrophy, a study has demonstrated that the overexpression of an inactive variant of OGA in transgenic mice causes muscle atrophy, as well as accumulation and activation of proapoptotic factors [Huang et al, ].…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells

Massaccesi

Goi

Tringali

et al. 2016

J of Cellular Biochemistry

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Skeletal muscle atrophy is a well-known adverse effect of chronic treatment with glucocorticoids and it also occurs when stress conditions such as sepsis and cachexia increase the release of endogenous glucocorticoids. Although the mechanisms of action of these hormones have been elucidated, the possible molecular mechanisms causing atrophy are not yet fully understood. The involvement of the O-GlcNAcylation process has recently been reported in disuse atrophy. O-GlcNAcylation, a regulatory post-translational modification of nuclear and cytoplasmic proteins consists in the attachment of O-GlcNAc residues on cell proteins and is regulated by two enzymes: O-GlcNAc-transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation plays a crucial role in many cellular processes and it seems to be related to skeletal muscle physiological function. The aim of this study is to investigate the involvement of O-GlcNAcylation in glucocorticoid-induced atrophy by using an "in vitro" model, achieved by treatment of C2C12 with 10 μM dexamethasone for 48 h. In atrophic condition, we observed that O-GlcNAc levels in cell proteins increased and concomitantly protein phosphorylation on serine and threonine residues decreased. Analysis of OGA expression at mRNA and protein levels showed a reduction in this enzyme in atrophic myotubes, whereas no significant changes of OGT expression were found. Furthermore, inhibition of OGA activity by Thiamet G induced atrophy marker expression. Our current findings suggest that O-GlcNAcylation is involved in dexamethasone-induced atrophy. In particular, we propose that the decrease in OGA content causes an excessive and mostly durable level of O-GlcNAc residues on sarcomeric proteins that might modify their function and stability. J. Cell. Biochem. 117: 1833-1842, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells

Massaccesi

Goi

Tringali

et al. 2016

J of Cellular Biochemistry

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“…For example, over-expression of OGT in muscle and adipose tissue causes insulin resistance and impairs glucose transport, respectively [21] , [22] . In addition, overexpression of OGA, which eliminates O-GlcNAcylation, impairs myogenesis and induces muscle atrophy [23] , [24] . These findings suggest that O-GlcNAcylation may be part of a complex signaling mechanism within skeletal muscle that is responsible for monitoring cellular nutrient availability and conveying this information to downstream targets to induce metabolic adaptation.…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity

Shi

Munk

Nielsen

et al. 2018

Molecular Metabolism

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ObjectiveGiven that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle.MethodsWe assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses.ResultsWe found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2).ConclusionsElevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders.

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“…By the way, through OGA manipulation in C2C12 cells, O-GlcNAcylation seemed to be a negative regulator of the myogenesis. This conclusion is reinforced by the overexpression of an inactive OGA variant and the increase of O-GlcNAcylation in a rat model inducing skeletal muscle atrophy ( 116 ). In contrast, a skeletal muscle specific OGT knockout in mice, leading to a global decrease of O-GlcNAcylation in the tissue, did not induce muscle hypertrophy ( 65 ).…”

Section: O-glcnacylation and Skeletal Muscle Dysfunctionsmentioning

confidence: 97%

Involvement of O-GlcNAcylation in the Skeletal Muscle Physiology and Physiopathology: Focus on Muscle Metabolism

2018

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Skeletal muscle represents around 40% of whole body mass. The principal function of skeletal muscle is the conversion of chemical energy toward mechanic energy to ensure the development of force, provide movement and locomotion, and maintain posture. This crucial energy dependence is maintained by the faculty of the skeletal muscle for being a central place as a “reservoir” of amino acids and carbohydrates in the whole body. A fundamental post-translational modification, named O-GlcNAcylation, depends, inter alia, on these nutrients; it consists to the transfer or the removal of a unique monosaccharide (N-acetyl-D-glucosamine) to a serine or threonine hydroxyl group of nucleocytoplasmic and mitochondrial proteins in a dynamic process by the O-GlcNAc Transferase (OGT) and the O-GlcNAcase (OGA), respectively. O-GlcNAcylation has been shown to be strongly involved in crucial intracellular mechanisms through the modulation of signaling pathways, gene expression, or cytoskeletal functions in various organs and tissues, such as the brain, liver, kidney or pancreas, and linked to the etiology of associated diseases. In recent years, several studies were also focused on the role of O-GlcNAcylation in the physiology and the physiopathology of skeletal muscle. These studies were mostly interested in O-GlcNAcylation during muscle exercise or muscle-wasting conditions. Major findings pointed out a different “O-GlcNAc signature” depending on muscle type metabolism at resting, wasting and exercise conditions, as well as depending on acute or long-term exhausting exercise protocol. First insights showed some differential OGT/OGA expression and/or activity associated with some differential stress cellular responses through Reactive Oxygen Species and/or Heat-Shock Proteins. Robust data displayed that these O-GlcNAc changes could lead to (i) a differential modulation of the carbohydrates metabolism, since the majority of enzymes are known to be O-GlcNAcylated, and to (ii) a differential modulation of the protein synthesis/degradation balance since O-GlcNAcylation regulates some key signaling pathways such as Akt/GSK3β, Akt/mTOR, Myogenin/Atrogin-1, Myogenin/Mef2D, Mrf4 and PGC-1α in the skeletal muscle. Finally, such involvement of O-GlcNAcylation in some metabolic processes of the skeletal muscle might be linked to some associated diseases such as type 2 diabetes or neuromuscular diseases showing a critical increase of the global O-GlcNAcylation level.

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Muscle-specific overexpression of NCOAT^GK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy

Cited by 22 publications

References 57 publications

Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells

Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells

Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity

Involvement of O-GlcNAcylation in the Skeletal Muscle Physiology and Physiopathology: Focus on Muscle Metabolism

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Muscle-specific overexpression of NCOATGK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy

Cited by 22 publications

References 57 publications

Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells

Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells

Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity

Involvement of O-GlcNAcylation in the Skeletal Muscle Physiology and Physiopathology: Focus on Muscle Metabolism

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Muscle-specific overexpression of NCOAT^GK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy