O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology

Abstract

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.

Protein O-GlcNAcylation in Metabolic Modulation of Skeletal Muscle: A Bright but Long Way to Go

“…During low-to-moderate-intensity exercise, the main fuel sources supplying skeletal muscle are glucose and are heavily influenced by insulin and glucose utilization increases progressively with increasing exercise intensity until near maximum intensity [ 64 ]. Several recent studies have demonstrated that O -GlcNAcylation controls early glucose metabolism in skeletal muscle [ 48 , 72 , 88 , 89 ]. The fuel metabolism and energy homeostasis of skeletal muscle are greatly dependent on the glucose uptake and disposal.…”

“…Meanwhile, type IIb is mainly exist in rodents, and types IIa and IIx are classified in humans [ 164 ]. It is the metabolic and morphological phenotype of each skeletal muscle fiber type coupled with the essential regulation of O -GlcNAcylation on skeletal muscle metabolic homeostasis and structural and contractile properties leading to the unique fine characteristics of O -GlcNAcylation in each type of skeletal muscle fiber [ 48 , 72 , 144 , 165 , 166 ]. In fact, the modulation of O -GlcNAcylation, OGT and OGA in each muscle fiber type is completely different, which may be attributed to the patterns of metabolic and molecular responses unique to each skeletal muscle fiber type [ 167 ].…”

“…GNE mutations cause GNE myopathy such as hereditary inclusion body myopathy and distal myopathy with rimmed vacuoles, and O -GlcNAcylation of GNE at Thr 743 cooperates with the phosphorylation at the same site to affect its efficiency and activity of GNE [ 204 ]. However, the abnormal overall O -GlcNAcylation levels is the major pathogenic factors in skeletal muscle atrophy [ 48 , 205 ]. For example, disruption of OGA activity mediates hyper O -GlcNAcylation, leading to muscle atrophy [ 58 ].…”

“…In addition, O -GlcNAcylation homeostasis is essential for the maintenance of the normal physiological function of cells, tissues and organs. Abnormal O -GlcNAcylation levels are closely associated with the pathogenesis and progression of various diseases such as neurodegenerative diseases [ 42 ], cardiovascular diseases [ 43 , 44 ], aging [ 45 ], obesity [ 46 , 47 ], amyotrophy [ 48 ], cancers [ 49 ], diabetes and diabetic complications [ 50 ].…”

“…This suggests a unique and central physiological role for O -GlcNAcylation in skeletal muscle. Recent data also suggest that O -GlcNAcylation is involved in different cellular processes in skeletal muscle such as regulation of contractile and structural properties, maintenance of energy metabolic homeostasis, and mediation of insulin resistance [ 48 , 56 , 57 ]. Meanwhile, O -GlcNAcylation plays a potential role in many diseases related to skeletal muscle defects such as neuromuscular diseases and amyotrophy [ 58 , 59 ].…”