title: Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage.
abstract: Adult skeletal muscle regeneration results from activation, proliferation, and fusion of muscle stem cells, such as myogenic precursor cells. Macrophages are consistently present in regenerating skeletal muscles and participate into the repair process. The signals involved in the cross-talk between various macrophage populations and myogenic precursor cells have been only partially identified. In this study, we show a key role of inducible NO synthase (iNOS), expressed by classically activated macrophages in the healing of skeletal muscle. We found that, after sterile injury, iNOS expression is required for effective regeneration of the tissue, as myogenic precursor cells in the muscle of injured iNOS(-/-) mice fail to proliferate and differentiate. We also found that iNOS modulates inflammatory cell recruitment: damaged muscles of iNOS(-/-) animals express significantly higher levels of chemokines such as MIP2, MCP1, MIP-1α, and MCP1, and display more infiltrating neutrophils after injury and a persistence of macrophages at later time points. Finally, we found that iNOS expression in the injured muscle is restricted to infiltrating macrophages. To our knowledge, these data thus provide the first evidence that iNOS expression by infiltrating macrophages contributes to muscle regeneration, revealing a novel mechanism of inflammation-dependent muscle healing.
authors: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Elena
authors: E
authors: Rigamonti
authors: Thierry
authors: T
authors: Touvier
authors: Emilio
authors: E
authors: Clementi
authors: Angelo A
authors: AA
authors: Manfredi
authors: Silvia
authors: S
authors: Brunelli
authors: Patrizia
authors: P
authors: Rovere-Querini
mesh_terms: D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000276:immunology / Q000293:injuries*; D009135:Muscular Diseases / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012038:Regeneration / Q000235:genetics / Q000276:immunology; D014945:Wound Healing / Q000235:genetics / Q000276:immunology
chemical_list: D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse