Human Galectin-1 Improves Sarcolemma Stability and Muscle Vascularization in the mdx Mouse Model of Duchenne Muscular Dystrophy

Wuebbles, Ryan D.; Cruz, Vivian; Ry, Pam Van; Barraza-Flores, Pamela; Brewer, Paul Duffield; Jones, Peter L.; Burkin, Dean J.

doi:10.1016/j.omtm.2019.01.004

Cited by 10 publications

(14 citation statements)

References 43 publications

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“…The greater accumulation of Gal-1 on the plasma membrane and increased repair capacity at 10min provides evidence that treatment may stabilize membrane associated proteins involved in repair enough to overcome the lack of dysferlin. Temporal-spatial images and fluorescent quantification provide evidence that by 8h, lattice structures are forming which may further explain enhanced membrane stability and changes in protein interactions in LGMD2B (Fig 5C) [58,59]. Furthermore, Gal-1 induced lattice formations appears to correlate with sites of cellular fusion (Fig 5 and S3 Fig, S2 Video).…”

Section: Discussionmentioning

confidence: 82%

Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models

et al. 2020

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Limb-girdle muscular dystrophy type 2B (LGMD2B) is caused by mutations in the dysferlin gene, resulting in non-functional dysferlin, a key protein found in muscle membrane. Treatment options available for patients are chiefly palliative in nature and focus on maintaining ambulation. Our hypothesis is that galectin-1 (Gal-1), a soluble carbohydrate binding protein, increases membrane repair capacity and myogenic potential of dysferlin-deficient muscle cells and muscle fibers. To test this hypothesis, we used recombinant human galectin-1 (rHsGal-1) to treat dysferlin-deficient models. We show that rHsGal-1 treatments of 48 h-72 h promotes myogenic maturation as indicated through improvements in size, myotube alignment, myoblast migration, and membrane repair capacity in dysferlin-deficient myotubes and myofibers. Furthermore, increased membrane repair capacity of dysferlin-deficient myotubes, independent of increased myogenic maturation is apparent and co-localizes on the membrane of myotubes after a brief 10min treatment with labeled rHsGal-1. We show the carbohydrate recognition domain of Gal-1 is necessary for observed membrane repair. Improvements in membrane repair after only a 10 min rHsGal-1treatment suggest mechanical stabilization of the membrane due to interaction with glycosylated membrane bound, ECM or yet to be identified ligands through the CDR domain of Gal-1. rHsGal-1 shows calcium-independent membrane repair in dysferlin-deficient and wild-type myotubes and myofibers. Together our novel results reveal Gal-1 mediates disease pathologies through both changes in integral myogenic protein expression and mechanical membrane stabilization.

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Section: Discussionmentioning

confidence: 82%

Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models

et al. 2020

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“…Administration of recombinant galectin-1 has recently been shown to improve muscle function in a mouse model of muscular dystrophy (14). Therefore, we next investigated the ability of galectin- produced ~3-fold average overexpression by western-blot analysis (data not shown).…”

Section: In Vivo Galectin-1 Gain-of-function Increases Muscle Massmentioning

confidence: 99%

“…Analysis of immortalized healthy and dystrophic human muscle cells with lectin histochemistry has recently revealed several changes in lectin binding, suggesting discrete changes in glycosylation or glycoprotein abundance ( 13 ). Excitingly, administration of recombinant galectin-1 in a genetic mouse model of muscular dystrophy (newborn mdx mice) displays improved muscle function and sarcolemmal integrity, suggesting critical roles of galectin-1 in myogenesis ( 14 ). These experiments are encouraging as they highlight new potential treatment options for a variety of muscle diseases.…”

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confidence: 99%

Integrated Glycoproteomics Identifies a Role of N-Glycosylation and Galectin-1 on Myogenesis and Muscle Development

Blazev

Ashwood

Abrahams

et al. 2021

Molecular & Cellular Proteomics

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Many cell surface and secreted proteins are modified by the covalent addition of glycans that play an important role in the development of multicellular organisms. These glycan modifications enable communication between cells and the extracellular matrix via interactions with specific glycan-binding lectins and the regulation of receptor-mediated signaling. Aberrant protein glycosylation has been associated with the development of several muscular diseases suggesting essential glycan- and lectin-mediated functions in myogenesis and muscle development but our molecular understanding of the precise glycans, catalytic enzymes and lectins involved remain only partially understood. Here, we quantified dynamic remodeling of the membrane-associated proteome during a time-course of myogenesis in cell culture. We observed wide-spread changes in the abundance of several important lectins and enzymes facilitating glycan biosynthesis. Glycomics-based quantification of released N-linked glycans confirmed remodeling of the glycome consistent with the regulation of glycosyltransferases and glycosidases responsible for their formation including a previously unknown di-galactose-to-sialic acid switch supporting a functional role of these glycoepitopes in myogenesis. Furthermore, dynamic quantitative glycoproteomic analysis with multiplexed stable isotope labelling and analysis of enriched glycopeptides with multiple fragmentation approaches identified glycoproteins modified by these regulated glycans including several integrins and growth factor receptors. Myogenesis was also associated with the regulation of several lectins most notably the up-regulation of galectin-1 (LGALS1). CRISPR/Cas9-mediated deletion of Lgals1 inhibited differentiation and myotube formation suggesting an early functional role of galectin-1 in the myogenic program. Importantly, similar changes in N-glycosylation and the up-regulation of galectin-1 during postnatal skeletal muscle development were observed in mice. Treatment of new-born mice with recombinant adeno-associated viruses to overexpress galectin-1 in the musculature resulted in enhanced muscle mass. Our data form a valuable resource to further understand the glycobiology of myogenesis and will aid the development of intervention strategies to promote healthy muscle development or regeneration.

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Section: In Vivo Galectin-1 Gain-of-function Increases Muscle Massmentioning

confidence: 99%

“…Galectins form a family of 15 members that bind to galactose via conserved carbohydrate binding domains (CBDs) (63).Galectin-1 is a prototypical galectin containing a single CBD that form dimers while galectin-3contains an extended N-terminal domain with the ability to form pentamers(64). Administration of recombinant galectin-1 to the mdx mouse model of muscle dystrophy increased utrophin and integrin expression, and improved skeletal muscle function(14). Furthermore, enhanced muscle function has also been observed with exogenous galectin-3 expression in a similar mdx mouse model(65).…”

mentioning

confidence: 99%

Integrated glycoproteomics identifies a role ofN-glycosylation and galectin-1 on myogenesis and muscle development

Blazev

Ashwood

Abrahams

et al. 2020

Preprint

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ABSTRACTMany cell surface and secreted proteins are modified by the covalent addition of glycans that play an important role in the development of multicellular organisms. These glycan modifications enable communication between cells and the extracellular matrix via interactions with specific glycan-binding lectins and the regulation of receptor-mediated signaling. Aberrant protein glycosylation has been associated with the development of several muscular diseases suggesting essential glycan- and lectin-mediated functions in myogenesis and muscle development but our molecular understanding of the precise glycans, catalytic enzymes and lectins involved remain only partially understood. Here, we quantified dynamic remodeling of the membrane-associated proteome during a time-course of myogenesis in cell culture. We observed wide-spread changes in the abundance of several important lectins and enzymes facilitating glycan biosynthesis. Glycomics-based quantification of released N-linked glycans confirmed remodeling of the glycome consistent with the regulation of glycosyltransferases and glycosidases responsible for their formation including a previously unknown di-galactose-to-sialic acid switch supporting a functional role of these glycoepitopes in myogenesis. Furthermore, dynamic quantitative glycoproteomic analysis with multiplexed stable isotope labelling and analysis of enriched glycopeptides with multiple fragmentation approaches identified glycoproteins modified by these regulated glycans including several integrins and growth factor receptors. Myogenesis was also associated with the regulation of several lectins most notably the up-regulation of galectin-1 (LGALS1). CRISPR/Cas9-mediated deletion of Lgals1 inhibited differentiation and myotube formation suggesting an early functional role of galectin-1 in the myogenic program. Importantly, similar changes in N-glycosylation and the up-regulation of galectin-1 during postnatal skeletal muscle development were observed in mice. Treatment of new-born mice with recombinant adeno-associated viruses to overexpress galectin-1 in the musculature resulted in enhanced muscle mass. Our data form a valuable resource to further understand the glycobiology of myogenesis and will aid the development of intervention strategies to promote healthy muscle development or regeneration.

show abstract

Human Galectin-1 Improves Sarcolemma Stability and Muscle Vascularization in the mdx Mouse Model of Duchenne Muscular Dystrophy

Cited by 10 publications

References 43 publications

Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models

Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models

Integrated Glycoproteomics Identifies a Role of N-Glycosylation and Galectin-1 on Myogenesis and Muscle Development

Integrated glycoproteomics identifies a role ofN-glycosylation and galectin-1 on myogenesis and muscle development

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