title: Dynamic changes in heparan sulfate during muscle differentiation and ageing regulate myoblast cell fate and FGF2 signalling.
abstract: Satellite cells (SCs) are skeletal muscle stem cells residing quiescent around healthy muscle fibres. In response to injury or disease SCs activate, proliferate and eventually differentiate and fuse to one another to form new muscle fibres, or to existing damaged fibres to repair them. The sulfated polysaccharide heparan sulfate (HS) is a highly variable biomolecule known to play key roles in the regulation of cell fate decisions, though the changes that muscle HS undergoes during SC differentiation are unknown. Here we show that the sulfation levels of HS increase during SC differentiation; more specifically, we observe an increase in 6-O and 2-O-sulfation in N-acetylated disaccharides. Interestingly, a specific increase in 6-O sulfation is also observed in the heparanome of ageing muscle, which we show leads to promotion of FGF2 signalling and satellite cell proliferation, suggesting a role for the heparanome dynamics in age-associated loss of quiescence. Addition of HS mimetics to differentiating SC cultures results in differential effects: an oversulfated HS mimetic increases differentiation and inhibits FGF2 signalling, a known major promoter of SC proliferation and inhibitor of differentiation. In contrast, FGF2 signalling is promoted by an N-acetylated HS mimetic, which inhibits differentiation and promotes SC expansion. We conclude that the heparanome of SCs is dynamically regulated during muscle differentiation and ageing, and that such changes might account for some of the phenotypes and signalling events that are associated with these processes.
authors: Department of Biochemistry, Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom.
authors: R S
authors: RS
authors: Ghadiali
authors: Department of Biochemistry, Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom.
authors: S E
authors: SE
authors: Guimond
authors: Department of Biochemistry, Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom.
authors: J E
authors: JE
authors: Turnbull
authors: Department of Biochemistry, Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom. Electronic address: pisconti@liverpool.ac.uk.
authors: A
authors: A
authors: Pisconti
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004187:Disaccharides; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate