title: Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury.
abstract: Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2-/- and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar. Nevertheless, edema and neutrophil accumulation were significantly elevated in CCR2-/- compared with WT mice at day 1 post-FAE and fewer macrophages were present at day 3. MCP-1 levels in post-ischemic calf muscle of CCR2-/- animals were significantly elevated over baseline through 14 days post-FAE and were higher than WT mice at days 1, 7, and 14. In addition, CCR2-/- mice exhibited impaired muscle regeneration, decreased muscle fiber size, and increased intermuscular adipocytes with similar capillaries/mm(2) postinjury. Finally, the transcription factors, MyoD and signal transducers of and activators of transcription-3 (STAT3), were significantly increased above baseline but did not differ significantly between groups at any time point post-FAE. These findings suggest that increases in MCP-1, and possibly, MyoD and STAT3, may modulate molecular signaling in CCR2-/- mice during inflammatory and regenerative events. Furthermore, alterations in neutrophil and macrophage recruitment in CCR2-/- mice may critically alter the normal progression of downstream regenerative events in injured skeletal muscle and may direct myogenic precursor cells in the regenerating milieu toward an adipogenic phenotype.
authors.affiliation: Univ. of Texas Health Science Center, 7703 Floyd Curl Dr., MC 7741, San Antonio, TX 78229-3900, USA.
authors.forename: Verónica
authors.initials: V
authors.lastname: Contreras-Shannon
authors.forename: Oscar
authors.initials: O
authors.lastname: Ochoa
authors.forename: Sara M
authors.initials: SM
authors.lastname: Reyes-Reyna
authors.forename: Dongxu
authors.initials: D
authors.lastname: Sun
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Linda M
authors.initials: LM
authors.lastname: McManus
authors.forename: Paula K
authors.initials: PK
authors.lastname: Shireman
mesh_terms: D017667:Adipocytes / Q000473:pathology*; D000818:Animals; D002196:Capillaries / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000378:metabolism; D006614:Hindlimb; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D017570:MyoD Protein / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D017570:MyoD Protein; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse