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

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 transcription3 ( 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.