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Am J Pathol. 2014 Apr;184(4):1167-1184. doi: 10.1016/j.ajpath.2013.12.020. Epub 2014 Feb 11.

Altered macrophage phenotype transition impairs skeletal muscle regeneration.

Author information

1
Department of Surgery, University of Texas Health Science Center, San Antonio, Texas.
2
Department of Surgery, University of Texas Health Science Center, San Antonio, Texas; Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas.
3
Department of Pathology, University of Texas Health Science Center, San Antonio, Texas; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas.
4
Department of Surgery, University of Texas Health Science Center, San Antonio, Texas; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas; The South Texas Veterans Health Care System, San Antonio, Texas. Electronic address: shireman@uthscsa.edu.

Abstract

Monocyte/macrophage polarization in skeletal muscle regeneration is ill defined. We used CD11b-diphtheria toxin receptor transgenic mice to transiently deplete monocytes/macrophages at multiple stages before and after muscle injury induced by cardiotoxin. Fat accumulation within regenerated muscle was maximal when ablation occurred at the same time as cardiotoxin-induced injury. Early ablation (day 1 after cardiotoxin) resulted in the smallest regenerated myofiber size together with increased residual necrotic myofibers and fat accumulation. However, muscle regeneration after late (day 4) ablation was similar to controls. Levels of inflammatory cells in injured muscle following early ablation and associated with impaired muscle regeneration were determined by flow cytometry. Delayed, but exaggerated, monocyte [CD11b(+)(CD90/B220/CD49b/NK1.1/Ly6G)(-)(F4/80/I-Ab/CD11c)(-)Ly6C(+/-)] accumulation occurred; interestingly, Ly6C(+) and Ly6C(-) monocytes were present concurrently in ablated animals and control mice. In addition to monocytes, proinflammatory, Ly6C(+) macrophage accumulation following early ablation was delayed compared to controls. In both groups, CD11b(+)F4/80(+) cells exhibited minimal expression of the M2 markers CD206 and CD301. Nevertheless, early ablation delayed and decreased the transient accumulation of CD11b(+)F4/80(+)Ly6C(-)CD301(-) macrophages; in control animals, the later tissue accumulation of these cells appeared to correspond to that of anti-inflammatory macrophages, determined by cytokine production and arginase activity. In summary, impairments in muscle regeneration were associated with exaggerated monocyte recruitment and reduced Ly6C(-) macrophages; the switch of macrophage/monocyte subsets is critical to muscle regeneration.

PMID:
24525152
PMCID:
PMC3969996
DOI:
10.1016/j.ajpath.2013.12.020
[Indexed for MEDLINE]
Free PMC Article

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