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* Department of Histology and Medical Embryology, CE-BEMM and Interuniversity Institute of Myology, University of Rome "La Sapienza," Rome, Italy;
Neuroimmunology Unit, Santa Lucia Foundation Scientific Institute, Rome, Italy;
IRCCS San Raffaele, Rome, Italy;
EMBL Mouse Biology Program, Monterotondo, Italy;
|| Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College London, London, UK; and
¶ Edith Cowan University, Perth, Western Australia, Australia
2Correspondence: Department of Histology and Medical Embryology, University of Rome "La Sapienza," Via A. Scarpa, 14 Rome 00161, Italy. E-mail: antonio.musaro{at}uniroma1.it
Muscle regeneration following injury is characterized by myonecrosis accompanied by local inflammation, activation of satellite cells, and repair of injured fibers. The resolution of the inflammatory response is necessary to proceed toward muscle repair, since persistence of inflammation often renders the damaged muscle incapable of sustaining efficient muscle regeneration. Here, we show that local expression of a muscle-restricted insulin-like growth factor (IGF)-1 (mIGF-1) transgene accelerates the regenerative process of injured skeletal muscle, modulating the inflammatory response, and limiting fibrosis. At the molecular level, mIGF-1 expression significantly down-regulated proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, and modulated the expression of CC chemokines involved in the recruitment of monocytes/macrophages. Analysis of the underlying molecular mechanisms revealed that mIGF-1 expression modulated key players of inflammatory response, such as macrophage migration inhibitory factor (MIF), high mobility group protein-1 (HMGB1), and transcription NF-
B. The rapid restoration of injured mIGF-1 transgenic muscle was also associated with connective tissue remodeling and a rapid recovery of functional properties. By modulating the inflammatory response and reducing fibrosis, supplemental mIGF-1 creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair.—Pelosi, L., Giacinti, C., Nardis, C., Borsellino, G., Rizzuto, E., Nicoletti, C., Wannenes, F., Battistini, L., Rosenthal, N., Molinaro, M., Musarò, A. Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines.
Key Words: fibrosis • inflammatory response • injury
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