Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines.
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-kappaB. 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
Laura
L
Department of Histology and Medical Embryology, University of Rome La Sapienza, Via A. Scarpa, 14 Rome 00161, Italy.
Giacinti
Cristina
C
Nardis
Chiara
C
Borsellino
Giovanna
G
Rizzuto
Emanuele
E
Nicoletti
Carmine
C
Wannenes
Francesca
F
Battistini
Luca
L
Rosenthal
Nadia
N
Molinaro
Mario
M
Musarò
Antonio
A
D000818:Animals; D001483:Base Sequence; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018836:Inflammation Mediators / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D007334:Insulin-Like Growth Factor I