Abstract
Regenerative mechanisms that regulate intramuscular motor innervation are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed an unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) triggered its expression exclusively at the early differentiation phase. In order to advance this concept, the present study described that transmembrane heparan/chondroitin sulfate proteoglycans syndecan-2, 4 may be the plausible receptor candidates for HGF and FGF2 to signal Sema3A expression. Results showed that mRNA expression of syndecan-2, 4 was abundant (two magnitudes higher than syndecan-1, 3) in early-differentiated myoblasts and their in vitro knockdown diminished the HGF/FGF2-induced expression of Sema3A down to a baseline level. Pretreatment with heparitinase and chondroitinase ABC decreased the HGF and FGF2 responses, respectively, in non–knockdown cultures, supporting a possible model that HGF and FGF2 may bind to heparan and chondroitin sulfate chains of syndecan-2, 4 to signal Sema3A expression. The findings, therefore, extend our understanding that HGF/FGF2-syndecan-2, 4 association may stimulate a burst of Sema3A secretion by myoblasts recruited to the site of muscle injury; this would ensure a coordinated delay in the attachment of motoneuron terminals onto fibers early in muscle regeneration, and thus synchronize the recovery of muscle fiber integrity and the early resolution of inflammation after injury with reinnervation toward functional recovery.
Highlights
Myogenesis and remodeling of neuromuscular connections are both critical for restoring muscle contractile properties during muscle regeneration
We found that satellite cells, resident myogenic stem cells found beneath the basal lamina in high density at neuromuscular junctions of mature fibers (Kelly 1978; Wokke et al 1989; Bischoff and FranziniArmstrong 2004), upregulate a secreted potent neural chemorepellent, semaphorin 3A (Sema3A, referred to as SemaIII, SemD, and collapsing) (Tanelian et al 1997; Goodman et al 1999; Kuhn et al 1999; Kawasaki et al 2002; Ieda et al 2007; Moret et al 2007) in the early differentiation phase of gastrocnemius muscle regeneration after injury by crush or cardiotoxin injection (Tatsumi et al 2009; Sato et al 2013)
The purpose of this study was to examine the nature of possible membrane receptor(s) for hepatocyte growth factor (HGF) and FGF2 which each impact Sema3A upregulation in early-differentiated satellite cells
Summary
Myogenesis and remodeling of neuromuscular connections are both critical for restoring muscle contractile properties during muscle regeneration. The physiological significance of these findings was confirmed by in vivo experiments of growth factors in extracellular wound fluid that found active HGF and FGF2 prevalent 4–6 days after crush injury of rat gastrocnemius muscle, while TGF-b3 increased at 12 days (Do et al 2012). These results emphasized a plausible role for HGF and FGF2 in the time-coordinated upregulation of Sema3A expression that could ensure the chemorepulsive events necessary to synchronize a delay in neurite sprouting and attachment of motoneuron terminals onto regenerating fibers. There is still a critical need to explore the molecular mechanisms of HGF/FGF2-induced Sema3A upregulation
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