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J Physiol Volume 586, Number 16, 3991-4004, August 15, 2008 DOI: 10.1113/jphysiol.2008.152090
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SKELETAL MUSCLE AND EXERCISE

CC family chemokines directly regulate myoblast responses to skeletal muscle injury

 Linda Yahiaoui1,2, Dusanka Gvozdic1,2, Gawiyou Danialou1,2, Matthias Mack3 and Basil J. Petrof1,2

1 Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada H2X 2P2
2 Department of Medicine, Respiratory Division, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1
3 Medical Policlinic, University of Munich, Munich, Germany

Chemokines have been implicated in the promotion of leucocyte trafficking to diseased muscle. The purpose of this study was to determine whether a subset of inflammatory chemokines are able to directly drive myoblast proliferation, an essential early component of muscle regeneration, in a manner which is entirely independent of leucocytes. Cultured myoblasts (C2C12) were exposed to monocyte chemoattractant protein-1 (MCP-1; CCL2), macrophage inflammatory protein-1{alpha} (MIP-1{alpha}; CCL3) or MIP-1β (CCL4). All chemokines induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and greatly increased myoblast proliferative responses. Chemokine-induced myoblast proliferation was abolished by pertussis toxin and the MEK1/2 inhibitor U0126, implicating both G{alpha}i-coupled receptors and ERK1/2-dependent signalling. Myoblasts expressed receptors for all of the chemokines tested, and mitogenic responses were specifically inhibited by antibodies directed against CC family chemokine receptors 2 and 5 (CCR2 and CCR5). Within an in vitro myogenic wound healing assay devoid of leucocytes, all chemokines significantly accelerated the time course of myoblast wound closure after mechanical injury. Injections of MCP-1 into cardiotoxin-injured skeletal muscles in vivo also suppressed expression of the differentiation marker myogenin, consistent with a mitogenic effect. Taken together, our results indicate that CC chemokines have potent and direct effects on myoblast behaviour, thus indicating a novel role in muscle repair beyond leucocyte chemoattraction. Therefore, interventions aimed at modulating the balance between myoblast and leucocyte effects of CC chemokines in injured muscle could represent a novel strategy for the treatment of destructive muscle pathologies.

(Received 1 February 2008; accepted after revision 14 June 2008; first published online 19 June 2008)
Corresponding author B. J. Petrof: Meakins-Christie Laboratories, McGill University, 3626 St Urbain Street, Montreal, Quebec, Canada H2X 2P2.  Email: basil.petrof{at}mcgill.ca






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