Altered expression of ganglioside GM3 molecular species and a potential regulatory role during myoblast differentiation

Abstract

Edited by Gerald W. Hart Gangliosides (sialic acid-containing glycosphingolipids) help regulate many important biological processes, including cell proliferation, signal transduction, and differentiation, via formation of functional microdomains in plasma membranes. The structural diversity of gangliosides arises from both the ceramide moiety and glycan portion. Recently, differing molecular species of a given ganglioside are suggested to have distinct biological properties and regulate specific and distinct biological events. Elucidation of the function of each molecular species is important and will provide new insights into ganglioside biology. Gangliosides are also suggested to be involved in skeletal muscle differentiation; however, the differential roles of ganglioside molecular species remain unclear. Here we describe striking changes in quantity and quality of gangliosides (particularly GM3) during differentiation of mouse C2C12 myoblast cells and key roles played by distinct GM3 molecular species at each step of the process. Glycosphingolipids (GSLs)3 are constituents of eukaryotic cell membranes located exclusively on the outer leaflet of the plasma membrane. Gangliosides, a subgroup of GSLs having one or more sialic acid residues, are involved in regulation of numerous cell biological events, including development, trafficking, signaling, and cellular interactions. Gangliosides have pathophysiological functions in diseases such as cancer, neurodegenerative disorders, and diabetes (1, 2). Sialic acid plays a key role in the biological activities of gangliosides (3). For example, we demonstrated that localization of insulin receptor in caveolae is disrupted by elevated levels of endogenous GM3 during the state of insulin resistance. This effect is due to electrostatic interaction between the lysine residue of insulin receptor (Lys-944) and the carboxyl group of sialic acid of GM3 (4 -8).The structural diversity of GSLs arises from both the ceramide (Cer) moiety and glycan portion (Fig. 1). Cer is composed of sphingosine and a single acyl chain (Fig. 1B). Cer acyl chains vary in length of carbon backbone, degree of saturation, and the presence/absence of ␣-hydroxylation (9, 10).Additional structural diversity of gangliosides arises from sialic acid (acidic sugar molecule with characteristic ninecarbon backbone) in the glycan portion. The most common sialic acid in mammals is N-acetylneuraminic acid (Neu5Ac). The other common sialic acid, N-glycolylneuraminic acid (Neu5Gc), differs from Neu5Ac by the presence of an additional oxygen atom in the acyl group at position C5 (Fig. 1B). Further structural diversity of sialic acids results from combinations of this variation at position C5 with modifications of hydroxyl groups at positions C4, C7, C8, and C9 by acetate, lactate, sulfate, phosphate esters, or methyl ethers. Sialic acid modifications greatly alter the size, hydrophobicity, net charge, and enzymatic susceptibility of the parent compound (11). Such structural divergence generated by different combin...

Serum GM3(d18:1-16:0) and GM3(d18:1-24:1) levels may be associated with lymphoma: An exploratory study with haematological diseases

“…reported that the serum GM3(d18:1-20:0) level was significantly elevated in subjects with visceral fat accumulation accompanied with hyperglycemia and dyslipidemia among the GM3 molecular species we have measured in the present study, while GM3(d18:1-16:0) and GM3(d18:1-24:1) levels were not altered 13 . A basic study also demonstrated the possible physiological importance of GM3 molecular species; the GM3(d18:1-16:0) content increased and the GM3(d18:1-24:1) content decreased during differentiation of mouse C2C12 myoblast cells 21 . Further studies are needed to elucidate the specific roles of GM3 molecular species.…”

Pathophysiological Significance of GM3 Ganglioside Molecular Species With a Particular Attention to the Metabolic Syndrome Focusing on Toll-Like Receptor 4 Binding

“…Ganglioside GM3, produced by addition of sialic acid to LacCer ( Figure 1A ), is expressed mainly in adipose tissue and muscle in humans and mice, and liver and serum in humans ( Senn et al, 1989 ; Wentworth et al, 2016 ; Go et al, 2017 ; Inokuchi et al, 2018 ). GM3 expression in adipocytes is induced by stimulation of the inflammatory cytokines TNF-α and IL-1β, derived from tissue macrophages ( Tagami et al, 2002 ; Nagafuku et al, 2015 ).…”

Muscle transcriptional networks linked to resistance exercise training hypertrophic response heterogeneity

“…Presently, BACE2 was most highly correlated with LV 2 (MetaMEx Aerobic Training, see Figure 2 for other pathway associations). The role of GM2A in skeletal muscle is poorly understood; however, it is typically involved in cholesterol and ganglioside processing (36), and recent work has linked gangliosides to developmental processes in C2C12 myoblasts (10). PLIER clustered GM2A with Type I myofiber markers in LV 6.…”