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Title: The role of heparan sulfate in muscle differentiation and ageing
Author: Ghadiali, R.
ISNI:       0000 0004 6425 2864
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Postnatal growth and regeneration of skeletal muscles depend on the activity of satellite cells, resident muscle stem cells defined by their location between the basal lamina and the muscle fibre plasma membrane. In response to injury or disease satellite cells activate, proliferate and eventually differentiate and fuse to one another to form new muscle fibres, or to existing damaged fibres to repair them. The microenvironment surrounding satellite cells, called the satellite cell niche, plays a crucial role in muscle regeneration. Heparan sulfate (HS) is a highly negatively charged, sulfated polysaccharide present on the surface of almost all mammalian cells or residing in the extracellular matrix. HS is usually bound to a core protein termed heparan sulfate proteoglycans (HSPGs). The HS component of the HSPG exhibits a high level of structural variability since it can vary in chain length and notably, in the pattern of sulfation along the length of the HS chain, leading to distinct chemical properties. As a consequence, HS is able to interact with numerous proteins, and thus plays a key role in the regulation of multiple cell processes. A number of HSPGs are expressed in muscle precursors during embryonic development and in satellite cells during postnatal life. However, the changes that muscle HS undergoes during satellite cell differentiation are unknown. In this project, it is shown that the sulfation levels of HS increase during satellite cell-derived myoblast differentiation. Interestingly, a specific increase in 6-O sulfation is also observed in HS from ageing muscle, which is shown to lead to promotion of FGF2 signalling and satellite cell proliferation, suggesting a role for HS in age-associated loss of satellite cell quiescence. Addition of chemically modified heparins (referred to as HS mimetics) to differentiating satellite cell derived-myoblast cultures results in differential effects depending on the pattern and level of sulfation: an oversulfated HS mimetic inhibits FGF2 signalling, a known major promoter of myoblast proliferation and inhibitor of differentiation. In contrast, FGF2 signalling is promoted by an N-acetylated HS mimetic, which inhibits differentiation and promotes satellite cell-derived myoblast expansion. The effects of a new class of fully synthetic HS mimetics (referred to as HS mimetic clusters), has been investigated on differentiating satellite cell derived-myoblast cultures. Finally, a new HS mimetic cluster has been synthesised and tested for its effects on differentiating satellite cell-derived myoblast cultures. Overall, these HS mimetic clusters have differential effects on myoblast differentiation. Thus, it can be concluded that the HS complement of the satellite cell niche 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. Furthermore, a novel class of HS mimetic clusters may offer promising therapeutic candidates for HS-mediated signalling events in muscle ageing and disease.
Supervisor: Turnbull, J. ; Pisconti, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral