Motor activity affects adult skeletal muscle re‐innervation acting via tyrosine kinase receptors

Abstract

Recently, muscle expression of brain-derived neurotrophic factor (BDNF) mRNA and protein under activity control has been reported. BDNF is a neurotrophin known to be involved in axon sprouting in the CNS. Hence, we set out to study the effect of chronic treadmill mid-intensity running on adult rat muscle re-innervation, and to explore the involvement of BDNF and tropomyosin-related kinase (Trk) receptors. After nerve crush, muscle re-innervation was evaluated using intracellular recordings, tension recordings, immunostaining and Western blot analyses. An enhanced muscle multiple innervation was found in running rats that was fully reversed to control values blocking Trk receptors or interrupting the running activity. An increase in muscle multiple innervation was also found in sedentary rats treated with a selective TrkB receptor agonist. The expression of TrkB receptors by intramuscular axons was demonstrated, and increased muscle expression of BDNF was found in running animals. The increase in muscle multiple innervation was consistent with the faster muscle re-innervation that we found in running animals. We conclude that, when regenerating axons contact muscle cells, muscle activity progressively increases modulating BDNF and possibly other growth factors, which in turn, acting via Trk receptors, induce axon sprouting to re-innervate skeletal muscle.

Effects of moderate‐ and high‐intensity chronic exercise on brain‐derived neurotrophic factor expression in fast and slow muscles

“…In this study, we investigate whether BDNF expression in skeletal muscle is also activity‐dependent, so we used 2 training intensities. Our results provide a response to a recently published suggestion by Sartini et al …”

“…Skeletal muscle, which expresses several neurotrophins and acts as an abundant source of neurotrophic support throughout development, is of particular interest. Several stimuli, including exercise, electrical stimulation, and some diseases, such as diabetes, modify BDNF expression . The BDNF gene structure in rats consists of 9 promoters or exons that produce the same mature protein independently of the messenger RNA (mRNA) molecules .…”

“…Several stimuli, including exercise, electrical stimulation, and some diseases, such as diabetes, modify BDNF expression. 7,[11][12][13][14][15][16] The BDNF gene structure in rats consists of 9 promoters or exons 17 that produce the same mature protein independently of the messenger RNA (mRNA) molecules. 13,17,18 The expression of exon IV in neurons (exon III in the nomenclature proposed by Timmusk et al 19 ) is sensitive to cellular activity.…”

Functional evaluation of peripheral nerve regeneration and target reinnervation in animal models: a critical overview

“…The presence of MEPPs and EPSPs is regarded as evidence of innervation (Cuppini, 1993). This electrophysiological method provides reliable information about synaptic efficacy and maturation at different times from nerve lesion (recorded MEPP frequency, EPSP amplitude and synapse fatiguability), and extension and resolution of nerve sprouting and of multiple innervation (two or more EPSPs recorded) of reinnervated muscle cells (Cuppini et al, 1998;Costanzo et al, 1999;Sartini et al, 2013). The technique is useful for evaluating detailed neuromuscular function, although it needs expertise and requires the animals to be killed at selected time points of reinnervation.…”

Failed reinnervation in aging skeletal muscle

“…Furthermore, forced over-expression of the neurotrophins BDNF, glial-derived neurotrophic factor ( GDNF ) and nerve growth factor ( NGF ) in muscle facilitate axonal sprouting and reinnervation following surgical denervation [13]. Similarly, the exercise-induced enhancement of reinnervation following nerve crush injury is dependent upon muscle BDNF signaling [14]. As such, examination of neurotrophins involved in reinnervation and microRNAs (miRNAs) predicted to suppress neurotrophins could provide insights to the potential cause of failed reinnervation in very advanced age or at the least identify whether this pathway might represent a therapeutic target.…”