Abstract
Neuromuscular junction (NMJ) research is vital to advance the understanding of neuromuscular patho‐physiology and development of novel therapies for diseases associated with NM dysfunction. In vivo, the micro‐environment surrounding the NMJ has a significant impact on NMJ formation and maintenance via neurotrophic and differentiation factors that are secreted as a result of cross‐talk between muscle fibers and motor neurons. Recently we showed the formation of functional NMJs in vitro in a co‐culture of immortalized human myoblasts and motor neurons from rat‐embryo spinal‐cord explants, using a culture medium free from serum and neurotrophic or growth factors. The aim of this study was to assess how functional NMJs were established in this co‐culture devoid of exogenous neural growth factors. To investigate this, an ELISA‐based microarray was used to compare the composition of soluble endogenously secreted growth factors in this co‐culture with an a‐neural muscle culture. The levels of seven neurotrophic factors brain‐derived neurotrophic factor (BDNF), glial‐cell‐line‐derived neurotrophic factor (GDNF), insulin‐like growth factor‐binding protein‐3 (IGFBP‐3), insulin‐like growth factor‐1 (IGF‐1), neurotrophin‐3 (NT‐3), neurotrophin‐4 (NT‐4), and vascular endothelial growth factor (VEGF) were higher (p < 0.05) in the supernatant of NMJ culture compared to those in the supernatant of the a‐neural muscle culture. This indicates that the cross‐talk between muscle and motor neurons promotes the secretion of soluble growth factors contributing to the local microenvironment thereby providing a favourable regenerative niche for NMJs formation and maturation.
Highlights
Neuromuscular Junctions (NMJs) are the highly specialized peripheral synapses that translate neural signals received from motor neurons to contractile activity in skeletal muscle cells (Witzemann, 2006)
The micro-e nvironment surrounding the NMJ has a significant impact on NMJ formation and maintenance via neurotrophic and differentiation factors that are secreted as a result of cross-talk between muscle fibers and motor neurons
We found that the abundance of brain-d erived neurotrophic factor (BDNF), glial-cell-line-derived neurotrophic factor (GDNF), NT- 3, NT-4, vascular endothelial growth factor (VEGF), IGF-1, and IGFBP-3 were all higher in the co-culture system than in a-n eurally cultured myoblasts
Summary
Neuromuscular Junctions (NMJs) are the highly specialized peripheral synapses that translate neural signals received from motor neurons to contractile activity in skeletal muscle cells (Witzemann, 2006). During embryological myogenesis cross-talk between muscle fibers and motor neurons appears indispensable for the development and maintenance of the neuromuscular system (Cisterna et al, 2014) The significance of this cross-talk is reflected by the limited differentiation in vitro of a-neurally cultured skeletal muscle cells to non- contracting myotubes (Delaporte et al, 1986) that contrasts with highly differentiated contracting myotubes in co-cultured skeletal muscle cells and motor neurons (Saini et al, 2019). The interdependence of these tissues is further apparent when considering neurodegenerative disorders where damage or pathologies of peripheral nerves is associated with significant muscle wasting and degeneration (Tintignac et al, 2015). This could be orchestrated via the secretion of critical trophic factors released into their microenvironment
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