N-Glycolylneuraminic acid deficiency worsens cardiac and skeletal muscle pathophysiology in α-sarcoglycan-deficient mice

Martin, Paul T.; Camboni, Marybeth; Xu, Rui; Golden, Bethannie; Chandrasekharan, Kumaran; Wang, Chiou-Miin; Varki, Ajit; Janssen, Paul M. L.

doi:10.1093/glycob/cwt020

Cited by 15 publications

(15 citation statements)

References 39 publications

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“…) and the Scga‐null mouse (Martin et al . ), perhaps contributing to the phenotype differences between mouse models of muscular dystrophy and the human phenotype.…”

Section: Disease Modifiersmentioning

confidence: 99%

“…Of interest is the role of CMAH, a gene encoding CMP-Neu5Ac cytidine-5 0 -monophospho-N-acetylneuraminic acid hydroxylase, which generates Neu5GC, a common sialic acid modification in mammalian muscle (Varki 2010), with the exception of humans, where the function of this gene has been lost (Chou et al 1998;Irie et al 1998). The loss of this gene worsened the phenotype of both the mdx mouse model (Chandrasekharan et al 2010) and the Scga-null mouse (Martin et al 2013), perhaps contributing to the phenotype differences between mouse models of muscular dystrophy and the human phenotype.…”

Section: Disease Modifiersmentioning

confidence: 99%

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What do mouse models of muscular dystrophy tell us about the DAPC and its components?

Whitmore

Morgan

2014

Int J Experimental Path

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SUMMARYThere are over 30 mouse models with mutations or inactivations in the dystrophinassociated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated.

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“…) and the Scga‐null mouse (Martin et al . ), perhaps contributing to the phenotype differences between mouse models of muscular dystrophy and the human phenotype.…”

Section: Disease Modifiersmentioning

confidence: 99%

Section: Disease Modifiersmentioning

confidence: 99%

What do mouse models of muscular dystrophy tell us about the DAPC and its components?

Whitmore

Morgan

2014

Int J Experimental Path

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“…Therefore, a Cmah ‐null mouse ( Cmah −/− ) with the human‐like exon deletion was generated to provide a practical model for studying the immediate loss of CMAH as it would have happened in hominins ≈3 Ma. Cmah −/− mice have several human‐like phenotypes (Table ), including the induction of anti‐Neu5Gc antibodies, enhancement of cancer inflammation and progression of Neu5Gc containing tumors, enhanced immune clearance of recombinant Neu5Gc containing therapeutics, delayed skin wound healing, enhanced age‐related hearing loss, altered immune responses, sexual selection through Neu5Gc antigenicity, altered susceptibility to metabolic disorders, altered susceptibility to muscular dystrophy, and a xeno‐antibody response against the vascular endothelium after nutritional incorporation of Neu5Gc …”

Section: A Mouse Model For Human Cmah Lossmentioning

confidence: 99%

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

Okerblom

Varki

2017

ChemBioChem

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About 2–3 million years ago, Alu‐mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation through female anti‐Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzee. Although the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxy groups at most cell surfaces remains poorly understood, we do know that there are multiscale effects functionally relevant to both sides of the host–pathogen interface. Hominin CMAH loss might also contribute to understanding human evolution, at the time when our ancestors were starting to use stone tools, increasing their consumption of meat, and possibly hunting. Comparisons with chimpanzees within ethical and practical limitations have revealed some consequences of human CMAH loss, but more has been learned by using a mouse model with a human‐like Cmah inactivation. For example, such mice can develop antibodies against Neu5Gc that could affect inflammatory processes like cancer progression in the face of Neu5Gc metabolic incorporation from red meats, display a hyper‐reactive immune system, a human‐like tendency for delayed wound healing, late‐onset hearing loss, insulin resistance, susceptibility to muscular dystrophy pathologies, and increased sensitivity to multiple human‐adapted pathogens involving sialic acids. Further studies in such mice could provide a model for other human‐specific processes and pathologies involving sialic acid biology that have yet to be explored.

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“…Taken together, these past and present findings indicate that the change of sialic acid species from Neu5Ac to Neu5Gc is crucial for myogenic differentiation in mice. Deletion of Cmah in mice increased the severity of muscular dystrophy (44,45), suggesting that this gene is a genetic modifier of muscle homeostasis. Taken together, our results suggest that myoblasts regulate their differentiation by changing the metabolism of sialic acids, ceramide, and, consequently, gangliosides.…”

Section: Gm3 Molecular Species and Myoblast Differentiationmentioning

confidence: 99%

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

Veillon

et al. 2017

Journal of Biological Chemistry

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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...

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N-Glycolylneuraminic acid deficiency worsens cardiac and skeletal muscle pathophysiology in α-sarcoglycan-deficient mice

Cited by 15 publications

References 39 publications

What do mouse models of muscular dystrophy tell us about the DAPC and its components?

What do mouse models of muscular dystrophy tell us about the DAPC and its components?

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

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

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