DiMeN Doctoral Training Partnership: Understanding and targeting syndecan-3 signalling in muscle regeneration

Skeletal muscle is a highly dynamic tissue, where tissue homeostasis and regeneration are maintained by a resident population of muscle stem cells, also known as satellite cells. Extracellular signals play an important role in determining satellite cell fate, and thus their ability to regenerate injured muscle, a function that is impaired in ageing and in muscular dystrophy (https://www.ncbi.nlm.nih.gov/pubmed/21615681). Syndecans are transmembrane proteoglycans that act as co-receptors in the regulation of several signalling pathways. Syndecan-3 is expressed by satellite cells and its protein levels are increased in the muscle of patients with Duchenne muscular dystrophy (https://www.ncbi.nlm.nih.gov/pubmed/23738267). SCs from syndecan-3 null mice show altered proliferation kinetics and enhanced regeneration (https://www.ncbi.nlm.nih.gov/pubmed/20696709). Interestingly, genetic ablation of syndecan-3 in dystrophic, aged and repeatedly injured mice rescues impaired muscle regeneration and muscle pathology, suggesting that syndecan-3 functions as a negative regulator of muscle regeneration (https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-016-0104-8). These data identify syndecan-3 as a potential therapeutic target for muscular dystrophy and for the prevention of muscle ageing and muscle loss due to repeated injury (e.g. in athletes). The molecular mechanisms underlying syndecan-3 function in muscle regeneration are poorly understood. We have previously shown that in muscle stem cells syndecan-3 modulates Notch signalling (https://www.ncbi.nlm.nih.gov/pubmed/20696709), a major regulator of muscle stem cell homeostasis. However, preliminary data indicate that other signalling pathways are affected as well. Specifically, it appears that syndecan-3 plays a key role in the regulation of signalling mediated by the insulin-like growth factor 1 receptor (IGF-1R), which in turn regulates SC proliferation and differentiation (https://www.ncbi.nlm.nih.gov/pubmed/17947802).

Since other two members of the syndecan family, syndecan-1 and syndecan-4, directly interact with IGF-1R in epithelial cells, we hypothesise that syndecan-3 interacts with IGF-1R in SCs and regulates SC proliferation and differentiation via regulation of IGF-1R signalling. This project aims to test this hypothesis by using a range of approaches including: biochemistry, cell biology, live cell imaging, confocal microscopy, computational biology, Fluorescence Resonance Energy Transfer, mass spectrometry, bioinformatics tools for structural biology and protein expression and purification. We expect that this project will: (1) elucidate whether syndecan-3 inhibits or promotes IGF-1R signalling, (2) identify the molecular mechanisms that transduce such interaction (e.g. whether syndecan-3 and IGF-1R directly interact), (3) discover novel syndecan-3 binding partners, (4) develop pharmacologic tools to target syndecan-3-mediated signalling and improve muscle regeneration in ageing, chronic disease and repeated muscle injury. We also expect that the student will become proficient in several techniques ranging from biochemistry, to cell biology, bioinformatics and molecular biology and that he/she will develop intellectual and communication skills. Indeed, the project will offer the possibility to attend and present data at both national and international conferences.