Denervation and reinnervation of adult skeletal muscle modulate mRNA expression of neuregulin-1 and ErbB receptors.
Skeletal muscle atrophy represents one of the main causes of poor outcome of microsurgical nerve reconstruction. Recent studies have pointed to the importance of the neuregulin/ErbB signaling pathway in the development and regeneration of the neuromuscular system. Here, we show by immunohistochemistry, RT-PCR, and Western blotting analyses, in an in vivo model of adult skeletal muscle denervation/reinnervation, that expression of Neuregulin1 (NRG1) and ErbB receptors is regulated by the innervation condition. We found out that a significant upregulation of the alpha-, but not beta-, isoform of NRG1, as well as of ErbB2, ErbB3, and ErbB4-cyt1 isoform occurs as a consequence of denervation of flexor digitorum muscles of the rat forelimb by median nerve transection. Moreover, after tubulization median nerve repair, and consequent muscle reinnervation, all messengers of the NRG1/ErbB system are promptly downregulated. Therefore, our results suggest the existence of a alpha-NRG1-mediated autocrine and/or paracrine trophic loop in skeletal muscles that is activated after denervation and promptly deactivated after nerve reconstruction. This myotrophic loop is a promising therapeutic target for the prevention of muscle atrophy. Yet, the recent demonstration of a similar alpha-NRG1-mediated gliotrophic loop in denervated Schwann cells provides a possible explanation for the effectiveness of muscle conduits for tubulization nerve repair.
Nicolino
Silvia
S
Dipartimento di Biologia Animale e dell'Uomo, Università di Torino, Torino, Italy.
Panetto
Arianna
A
Raimondo
Stefania
S
Gambarotta
Giovanna
G
Guzzini
Matteo
M
Fornaro
Michele
M
Battiston
Bruno
B
Tos
Perluigi
P
Geuna
Stefano
S
Perroteau
Isabelle
I
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008475:Median Nerve / Q000502:physiology / Q000601:surgery*; D018613:Microscopy, Confocal; D008866:Microsurgery / Q000379:methods*; D009121:Muscle Denervation / Q000379:methods; D018482:Muscle, Skeletal / Q000294:innervation* / Q000473:pathology / Q000601:surgery; D009133:Muscular Atrophy / Q000235:genetics / Q000503:physiopathology; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases; D020127:Recovery of Function; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction
D005819:Genetic Markers; D006023:Glycoproteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C483804:Erbb2 protein, rat