OGT Protects Skeletal Muscle From Damage Through SIRT1 O-GlcNAcylation During Cold Stress

yu Cao, Meng Zhang,Ye Li,Jing jing Lu,Wanhui Zhou, Xiaoshuang Li,Hao Shi,Bin Xu,Shize Li

Research Square (Research Square)(2022)

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Abstract
Abstract BackgroundThe effect of cold stress on skeletal muscle metabolism is not clear, and skeletal muscle O-linked-N-acetylglucosaminylation(O-GlcNAcylation) is important for muscle energy homeostasis. So, we aimed to clarify the functional role of O-GlcNAcylation in skeletal muscle during cold stress.ResultsTo understand the functional role of O-GlcNAcylation in skeletal muscle, we ablated OGT and thus O-GlcNAcylation specifically in mouse skeletal muscle and subjected the mice to cold stress. Cold stress induced profound damages to skeletal muscle, reduced the content of mitochondria, and compromised mitochondrial functions. In response to cold stress, pathways involved in autophagy and mitophagy were upregulated, accompanied by an increase in OGT expression. Cold stress also enhanced protein acetylation and reduced the expression and activity of sirtuin 1 (SIRT1). Using C2C12 cells as the in vitro model, we showed that OGT could physically interact with SIRT1 and increased SIRT1 stability through O-GlcNAcylation. During cold stress, SIRT1 partially mediated OGT effect as the overexpression of wild-type but not O-GlcNAcylation site-mutated SIRT1 ameliorated cold stress syndrome.ConclusionsOverall, this study reveals a protective role of OGT-SIRT1 axis in skeletal muscle’s adaptation to cold stress, and our findings provide new avenues to combating stress-induced diseases.
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Key words
skeletal muscle,sirt1,cold,o-glcnacylation
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