The role of semaphorin3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibres

Abstract

Current research on skeletal muscle injury and regeneration highlights the crucial role of nerve-muscle interaction in the restoration of innervation during that process. Activities of muscle satellite or stem cells, recognized as the 'currency' of myogenic repair, have a pivotal role in these events, as shown by ongoing research. More recent investigation of myogenic signalling events reveals intriguing roles for semaphorin3A (Sema3A), secreted by activated satellite cells, in the muscle environment during development and regeneration. For example, Sema3A makes important contributions to regulating the formation of blood vessels, balancing bone formation and bone remodelling, and inflammation, and was recently implicated in the establishment of fibre-type distribution through effects on myosin heavy chain gene expression. This review highlights the active or potential contributions of satellite-cell-derived Sema3A to regulation of the processes of motor neurite ingrowth into a regenerating muscle bed. Successful restoration of functional innervation during muscle repair is essential; this review emphasizes the integrative role of satellite-cell biology in the progressive coordination of adaptive cellular and tissue responses during the injury-repair process in voluntary muscle.

Altered Satellite Cell Responsiveness and Denervation Implicated in Progression of Rotator-Cuff Injury

“…Considering the atrophic, denervated state of injured SS muscle, this confirmation that the neuro-chemorepellent was secreted, is not surprising. The finding of greater Sema3A protein localization in SS than control muscle is consistent with the observed increase in γ-AchR in SS muscle through western blot experiments, indicative of SS denervation, since SCs produce the neuro-chemorepellent; this secretion of Sema3A from SCs in early differentiation is proposed as a means of preventing innervation of very new fibers, synchronizing fiber differentiation with the process of innervation [ 24 , 25 ]. The present results are also consistent with previous findings in animal models of injury, including crush and toxic injection, that report increases in Sema3A following both mechanisms of injury [ 23 , 45 ].…”

“…The independent confirmation that ISDN activated SCs from the supraspinatus muscle provides strong support for using a NO-donor drug, possibly in combination with mechanical stretching (e.g., by exercise), to promote muscle growth. Finally, the activity of SCs and their potential role in the process of muscle reinnervation (via Sema3A) is a relatively new field of interest [ 24 , 25 ]. It was interesting to examine this phenomenon in denervated, injured, human SS muscle and find significantly more Sema3A protein localized to SCs in SS compared to control.…”

“…While the relationship between SC capacity for activation and the innervation status of SS after RCI is not understood, recent research has implicated SC signaling in the process of muscle reinnervation. SC have potential to influence axon growth and the reappearance of NMJs by their secretion of semaphorin 3A (Sema3A) [ 23 , 24 ]. Sema3A is a neural chemorepellent that is thought to coordinate the reconnection of motor axons with a differentiating fiber in a regenerating muscle [ 25 ].…”

“…Sema3A is a neural chemorepellent that is thought to coordinate the reconnection of motor axons with a differentiating fiber in a regenerating muscle [ 25 ]. The current model is that a decline in Sema3A would allow motor neurites to re-contact repaired fibers and possibly influence the fiber-type patterning of muscle [ 24 ], although this has not been investigated in human or pathological muscle.…”

Interference with SRF expression in skeletal muscles reduces peripheral nerve regeneration in mice

“…3-5) suggesting an inhibitory SC function in nerve regeneration. Interestingly, SCs secrete semaphorin family members such as Sema3A, a well-established regulator of axonal growth and regeneration 35 . Thus, future studies will have to address whether SCs influence nerve regeneration through semaphorin secretion.…”