Abstract
Neuregulin 1 (NRG1) is a growth factor produced by both peripheral nerves and skeletal muscle. In muscle, it regulates neuromuscular junction gene expression, acetylcholine receptor number, muscle homeostasis and satellite cell survival. NRG1 signalling is mediated by the tyrosine kinase receptors ErbB3 and ErbB4 and their co-receptors ErbB1 and ErbB2. The NRG1/ErbB system is well studied in nerve tissue after injury, but little is known about this system in skeletal muscle after denervation/reinnervation processes. Here, we performed a detailed time-course expression analysis of several NRG1 isoforms and ErbB receptors in the rat superficial digitorum flexor muscle after three types of median nerve injuries of different severities. We found that ErbB receptor expression was correlated with the innervated state of the muscle, with upregulation of ErbB2 clearly associated with the denervation state. Interestingly, the NRG1 isoforms were differently regulated depending on the nerve injury type, leading to the hypothesis that both the NRG1α and NRG1β isoforms play a key role in the muscle reaction to injury. Indeed, in vitro experiments with C2C12 atrophic myotubes revealed that both NRG1α and NRG1β treatment influences the best-known atrophic pathways, suggesting that NRG1 might play an anti-atrophic role.
Highlights
The innervation of skeletal muscle has a predominant role in muscle structural and functional maintenance
The aim of this study was to describe the modulation of the Neuregulin 1 (NRG1)/ErbB system in skeletal muscle after peripheral nerve injury
To investigate the molecular changes occurring in muscle during denervation and reinnervation, we took advantage of three nerve injury models characterized by different severities, namely denervation, crush injury and end-to-end repair
Summary
The innervation of skeletal muscle has a predominant role in muscle structural and functional maintenance. The stem cell pool in the muscle, the satellite cells, exit from their quiescent state and become active: they proliferate and differentiate into multi-nucleated myofibres. This mechanism tries to maintain the muscle mass until reinnervation. Neuregulin 1 (NRG1) is a trophic factor produced by nerves as well as by the muscle It is a member of the epidermal growth factor (EGF) family, and it mediates the crosstalk between motor axon and muscle, between terminal Schwann cells and motor axon, and between different muscle fibres[6]. To investigate the effects of NRG1α and NRG1β, in vitro stimulation experiments were performed using C2C12 cells as a model of atrophic myotubes
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