Abstract
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.
Highlights
Just over thirty years ago, the O-linked N-acetyl-β-Dglucosaminylation, termed O-GlcNAcylation, was discovered inside the mouse lymphocyte cells by Torres and Hart [1]
It was recently demonstrated that the global modulation of O-GlcNAcylation level in C2C12 skeletal muscle cells differentiated into myotubes led to the modulation of protein-protein interactions in multiprotein complexes; while this study focused on structural proteins, the proteomic data suggested that the glycolytic metabolon could be modulated by O-GlcNAcylation changes as well (Figure 1) [18]
In the past ten years, more and more studies concerned O-GlcNAcylation in the skeletal muscle physiology and physiopathology. This glycosylation is mostly related to glucose metabolism, and skeletal muscle is one of the largest consumers of glucose; in addition, numerous studies showed that skeletal muscle is essential for glucose homeostasis and insulin sensitivity
Summary
Just over thirty years ago, the O-linked N-acetyl-β-Dglucosaminylation, termed O-GlcNAcylation, was discovered inside the mouse lymphocyte cells by Torres and Hart [1] From this discovery, about 1,400 studies were focused on this field among hundreds of other known post-translational modifications. The GlcNAc moieties can be added and removed several times along the protein lifetime, and the turn-over is shorter than the protein backbone’s one This O-GlcNAc dynamic process could reply to many environmental conditions and physiological signals such as nutriment availability, especially from its UDP-GlcNAc donor, the last product of the Hexosamine Biosynthesis Pathway [13, 14]. This present review discusses the involvement of O-GlcNAcylation in skeletal muscle metabolism (in particular glucose metabolism), the impact of exercise on O-GlcNAcylation, and the potential role of this posttranslational modification in skeletal muscle in a context of disease such as type 2 diabetes and neuromuscular disorders
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