title: High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle.
abstract: High-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecules, favors tissue regeneration via recruitment and activation of leukocytes and stem cells. Here we demonstrate, in a model of acute sterile muscle injury, that regeneration is accompanied by active reactive oxygen species (ROS) production counterbalanced and overcome by the generation of antioxidant moieties. Mitochondria are initially responsible for ROS formation. However, they undergo rapid disruption with almost complete disappearance. Twenty-four hours after injury, we observed a strong induction of MURF1 and atrogin-1 ubiquitin ligases, key signals in activation of the proteasome system and induction of muscle atrophy. At later time points, ROS generation is maintained by nonmitochondrial sources. The antioxidant response occurs in both regenerating fibers and leukocytes that express high levels of free thiols and antioxidant enzymes, such as superoxide dismutase 1 (SOD1) and thioredoxin. HMGB1, a protein thiol, weakly expressed in healthy muscles, increases during regeneration in parallel with the antioxidant response in both fibers and leukocytes. A reduced environment may be important to maintain HMGB1 bioactivity. Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro. We propose that the early antioxidant response in regenerating muscle limits HMGB1 oxidation, thus allowing successful muscle regeneration.
authors.affiliation: Innate Immunity and Tissue Remodeling Unit, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Vezzoli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Castellani
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Corna
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castiglioni
authors.forename: Lidia
authors.initials: L
authors.lastname: Bosurgi
authors.forename: Antonella
authors.initials: A
authors.lastname: Monno
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000975:Antioxidants; D024243:HMGB1 Protein; D009124:Muscle Proteins; D017382:Reactive Oxygen Species; D044843:SKP Cullin F-Box Protein Ligases; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C486691:Fbxo32 protein, mouse; C499084:Trim63 protein, mouse