O-GlcNAcylation is a highly dynamic, reversible and atypical glycosylation that regulates the activity, biological function, stability, sublocation and interaction of target proteins. O-GlcNAcylation receives and coordinates different signal inputs as an intracellular integrator similar to the nutrient sensor and stress receptor, which target multiple substrates with spatio-temporal analysis specifically to maintain cellular homeostasis and normal physiological functions. Our review gives a brief description of O-GlcNAcylation and its only two processing enzymes and HBP flux, which will help to better understand its physiological characteristics of sensing nutrition and environmental cues. This nutritional and stress-sensitive properties of O-GlcNAcylation allow it to participate in the precise regulation of skeletal muscle metabolism. This review discusses the mechanism of O-GlcNAcylation to alleviate metabolic disorders and the controversy about the insulin resistance of skeletal muscle. The level of global O-GlcNAcylation is precisely controlled and maintained in the “optimal zone”, and its abnormal changes is a potential factor in the pathogenesis of cancer, neurodegeneration, diabetes and diabetic complications. Although the essential role of O-GlcNAcylation in skeletal muscle physiology has been widely studied and recognized, it still is underestimated and overlooked. This review highlights the latest progress and potential mechanisms of O-GlcNAcylation in the regulation of skeletal muscle contraction and structural properties.
Cold exposure is an unavoidable and severe challenge for people and animals residing in cold regions of the world, and may lead to hypothermia, drastic changes in systemic metabolism, and inhibition of protein synthesis. O‐linked‐N‐acetylglucoseaminylation (O‐GlcNAcylation) directly regulates the activity and function of target proteins involved in multiple biological processes by acting as a stress receptor and nutrient sensor. Therefore, our study aimed to examine whether O‐GlcNAcylation affected myogenic IL‐6 expression, regulation of energy metabolism, and promotion of survival in mouse skeletal muscle under acute cold exposure conditions. Total protein was extracted from C2C12 cells that had been cultured at 32°C for 3, 6, 9, and 12 h. Western blot analysis showed that mild hypothermia enhanced O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) expression. Furthermore, global OGT‐dependent glycosylation and interleukin‐6 (IL‐6) levels peaked 3 h after induction of mild hypothermia. Enhanced activation of the NF‐κB pathway was also observed in response to mild hypothermia. Alloxan and Thiamet G were used to reduce and increase global OGT glycosylation levels in C2C12 cells, respectively. Increased O‐GlcNAcylation was associated with significant upregulation of IL‐6 expression, as well as enhanced activity and nuclear translocation of p65, while decreased O‐GlcNAcylation had the opposite effect. In addition, increased O‐GlcNAcylation was associated with significantly increased glucose metabolism, and OGT‐mediated O‐GlcNAcylation of p65. We generated skeletal muscle‐specific OGT knockout mice and exposed them to cold at 4°C for 3 h per day for 1 week. OGT deficiency attenuated the O‐GlcNAcylation, activity, and nuclear translocation of p65, resulting in downregulation of IL‐6 in mouse skeletal muscle of mice exposed to cold conditions. Taken together, our data suggested that O‐GlcNAcylation of p65 enhanced p65 activity and nuclear translocation leading to the upregulation of IL‐6, which maintained energy homeostasis and promotes cell survival in mouse skeletal muscle during cold exposure.
RNA‐binding motif protein 3 (RBM3), an outstanding cold shock protein, is rapidly upregulated to ensure homeostasis and survival in a cold environment, which is an important physiological mechanism in response to cold stress. Meanwhile, RBM3 has multiple physiological functions and participates in the regulation of various cellular physiological processes, such as antiapoptosis, circadian rhythm, cell cycle, reproduction, and tumogenesis. The structure, conservation, and tissue distribution of RBM3 in human are demonstrated in this review. Herein, the multiple physiological functions of RBM3 were summarized based on recent research advances. Meanwhile, the cytoprotective mechanism of RBM3 during stress under various adverse conditions and its regulation of transcription were discussed. In addition, the neuroprotection of RBM3 and its oncogenic role and controversy in various cancers were investigated in our review.
O-GlcNAcylation is an atypical, dynamic and reversible O-glycosylation that is critical and abundant in metazoan. O-GlcNAcylation coordinates and receives various signaling inputs such as nutrients and stresses, thus spatiotemporally regulating the activity, stability, localization and interaction of target proteins to participate in cellular physiological functions. Our review discusses in depth the involvement of O-GlcNAcylation in the precise regulation of skeletal muscle metabolism, such as glucose homeostasis, insulin sensitivity, tricarboxylic acid cycle and mitochondrial biogenesis. The complex interaction and precise modulation of O-GlcNAcylation in these nutritional pathways of skeletal muscle also provide emerging mechanical information on how nutrients affect health, exercise and disease. Meanwhile, we explored the potential role of O-GlcNAcylation in skeletal muscle pathology and focused on its benefits in maintaining proteostasis under atrophy. In general, these understandings of O-GlcNAcylation are conducive to providing new insights into skeletal muscle (patho) physiology.
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