O‐GlcNAcylation as a regulator of the functional and structural properties of the sarcomere in skeletal muscle: An update review

Abstract

Although the O-GlcNAcylation process was discovered in 1984, its potential role in the physiology and physiopathology of skeletal muscle only emerged 20 years later. An increasing number of publications strongly support a key role of O-GlcNAcylation in the modulation of important cellular processes which are essential for skeletal muscle functions. Indeed, over a thousand of O-GlcNAcylated proteins have been identified within skeletal muscle since 2004, which belong to various classes of proteins, including sarcomeric proteins. In this review, we focused on these myofibrillar proteins, including contractile and structural proteins. Because of the modification of motor and regulatory proteins, the regulatory myosin light chain (MLC2) is related to several reports that support a key role of O-GlcNAcylation in the fine modulation of calcium activation parameters of skeletal muscle fibres, depending on muscle phenotype and muscle work. In addition, another key function of O-GlcNAcylation has recently emerged in the regulation of organization and reorganization of the sarcomere.Altogether, this data support a key role of O-GlcNAcylation in the homeostasis of sarcomeric cytoskeleton, known to be disturbed in many related muscle disorders.

Global O-GlcNAcylation changes impact desmin phosphorylation and its partition toward cytoskeleton in C2C12 skeletal muscle cells differentiated into myotubes

“…Moreover, O-GlcNAcylation was linked to the modulation of IFs, in particular vimentin 6 and keratin 8/18 filaments 5 , 36 , with a link between O-GlcNAcylation and cell survival in stress condition 34 . In skeletal muscle, O-GlcNAcylation extensively modifies other nucleocytoplasmic and mitochondrial proteins and also myofibrillar proteins 37 . We have previously demonstrated that motor and regulatory proteins are O-GlcNAcylated modulating so the contractile properties of skeletal muscle such as calcium activation parameters 30 , 38 – 41 .…”

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

“…To date, many O -GlcNAcylated contractile proteins and contractile-related regulatory proteins in sarcomere have been identified [ 67 ]. These key contractile proteins include actin, myosin, MLC and MHC, tropomyosin and troponin, etc.…”

“…These sites are located in the marginal of the carboxy terminal, which is closely related to the polymerization and the interaction of MHC [ 220 ]. Further evidence is that one of the sites is associated with a hereditary myosin myopathy because its mutation destroys the polymerization of myosin to myomesin, M protein and titin [ 67 ]. Unfortunately, although these specific O -GlcNAcylation changes are associated with calcium sensitivity, they have not been appreciated and studied, and precise O -GlcNAcylated site identification is lacking.…”

“…Many reports have shown that O -GlcNAcylation may play an equally crucial role in skeletal muscle physiology as phosphorylation [ 65 , 67 , 221 , 222 ]. Another possible mechanism is that O -GlcNAcylation plays its biological function by interacting with phosphorylation, as shown in Box 1 .…”

“…Meanwhile, O -GlcNAcylation plays a potential role in many diseases related to skeletal muscle defects, such as neuromuscular diseases and amyotrophy [ 63 , 64 , 65 ]. Moreover, a great quantity of O -GlcNAcylated contractile and structural proteins were identified in sarcomeres, such as actin and myosin [ 66 , 67 ]. O -GlcNAcylation is a physiological mediator of skeletal muscle, such as contractile and structural properties, and myocardial and smooth muscle are no exception [ 68 , 69 , 70 , 71 ].…”