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Objective: O-GlcNAcylation, a nutrient sensing pathway involved in a myriad of cellular processes, it plays a key role in metabolism homeostasis. Cold stress disturbs cellular metabolic and energy homeostasis and is one of the causes of stress-induced illnesses. It is reported that O-GlcNAcylation has been shown to be upregulated during cold stress. Skeletal muscle and its residential mitochondria play an important role in maintaining the metabolic homeostasis of the whole body. Nevertheless, the mechanism of which O-GlcNAcylation adapts to cold stress in skeletal muscle remains unknown.Methods: To characterize the effect of O-GlcNAcylation on mouse skeletal muscle during cold exposure, this research investigated the effects of skeletal muscle structure, function, mitochondrial homeostasis, the deacetylation activity of SIRT1, acetylation expression levels and oxidative stress levels in Ogt mKO mice by cold exposure (4 ℃, 3 h a day, for 1 week). In order to understand the mechanism of O-GlcNAcylation on skeletal muscle homeostasis under cold stress, C2C12 cells was used as a model in vitro. C2C12 cells were treated with OGT inhibitor (Alloxan) and OGA inhibitor (Thiamet G) to decrease and enhance O-GlcNAcylation signals in mild hypothermia, respectively, and then recapitulated in vivo phenotype. Finally, the interaction between OGT and SIRT1 was demonstrated, and the O-GlcNAcylation of SIRT1 played an important role in the imbalance of skeletal muscle homeostasis induced by cold exposure.Results: Results showed that in addition to enhance cold stress-induced mitochondrial abnormalities, cell senescence, and collagen accumulation, Ogt deficiency was found to induce autophagy, mitophagy and oxidative stress level in skeletal muscle during cold exposure. And the results showed that the expression level of SIRT1 was reduced, concomitant with increased expression and acetylation of FoxO1 in wild type mice challenged with cold stress. Because the depletion of Ogt further reduced SIRT1, and increased FoxO1 in muscle challenged with cold stress. Furthermore, this study showed that OGT had a physiological interaction with SIRT1. Thr160 and Ser161 sites of SIRT1 could be O-GlcNAcylation, and overexpression of SIRT1 saved mitochondrial defects in C2C12 cells caused by cold exposure.Conclusion: Cold stress can cause skeletal muscle damage, and O-GlcNAcylation of SIRT1 is an important protection mechanisms of skeletal muscle’s adaptation to cold stress.