Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury

Verónica Contreras-Shannon, Oscar Ochoa, Sara M. Reyes-Reyna, Dongxu Sun, Joel E. Michalek, William A. Kuziel, Linda M. McManus, Paula K. Shireman

Research output: Contribution to journalArticle

103 Scopus citations

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/mm2 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.

Original languageEnglish (US)
Pages (from-to)C953-C967
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 1 2007

Keywords

  • Adipocyte
  • Macrophage
  • MyoD
  • Myogenic progenitor cell
  • Neutrophil
  • Signal transducers of and activators of transcription-3

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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