title: Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment.
abstract: Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2-/- mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2-/- mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1-/- and CCR2-/- mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1-/- compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2-/- mice. Although tissue levels of MCP-5 were elevated in MCP-1-/- mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1-/- mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1-/- mice, and severely impaired in CCR2-/- mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1-/- mice exhibit an intermediate phenotype compared with CCR2-/- mice. Intermediate macrophage recruitment in MCP-1-/- mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1-/- mice.
authors.affiliation: Department of Surgery, The University of Texas Health Science Center San Antonio, San Antonio, TX 78229-3900, USA.
authors.forename: Carlo O
authors.initials: CO
authors.lastname: Martinez
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McHale
authors.forename: Jason T
authors.initials: JT
authors.lastname: Wells
authors.forename: Oscar
authors.initials: O
authors.lastname: Ochoa
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.forename: Linda M
authors.initials: LM
authors.lastname: McManus
authors.forename: Paula K
authors.initials: PK
authors.lastname: Shireman
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000633:toxicity; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D009135:Muscular Diseases / Q000139:chemically induced; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D013997:Time Factors
chemical_list: D054715:Cardiotoxins; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D054390:Receptors, CCR2