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Published online before print May 20, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1102528

Received for publication November 5, 2002.
Revised April 8, 2004.
Accepted for publication April 9, 2004.

Article

P-selectin inhibition suppresses muscle regeneration following injury

Wallace Baker ^*, Barbara A. St. Pierre Schneider ^*, Anhurunda Kulkarni ^*, Gloria Sloan , Robert Schaub , Joseph Sypek , and Joseph G. Cannon ^@

Departments of Medical Technology and Physiology, Medical College of Georgia, Augusta; *Noll Physiological Research Center, Pennsylvania State University, University Park; and Wyeth Research, Andover, Massachusetts

^@ To whom correspondence should be addressed. E-mail: jcannon{at}mcg.edu.

	Abstract

This investigation sought to determine if P-selectin-mediated mechanisms contributed to macrophage localization in damaged muscle, an essential process for muscle regeneration. Mice were injected intravenously (i.v.) with soluble P-selectin glycoprotein ligand-1 (sPSGL-1) at 5, 50, or 200 µg/mouse or with 100 µl vehicle alone, and then, lengthening contractions were induced in hindlimb plantar-flexor muscles. The contractions caused fiber damage in soleus muscles, with maximal invasion by CD11b⁺ mononuclear cells at 24 h post-injury and substantial accumulation of CD11b⁺ mononuclear cells in the extracellular matrix up to 7 days post-injury. sPSGL-1 treatment caused a dose-dependent decrease in the number of regenerating fibers (P=0.021), as determined by developmental myosin heavy chain (dMHC) expression. This expression was reduced 93% at 7 days post-injury by the highest dose of sPSGL-1, which had no significant influence on intrafiber or extracellular accumulation of cells expressing CD11b, a general marker for phagocytic cells. Additional mice were injected i.v. with 20 µg anti-P-selectin or isotype-control immunoglobulin G and were then subjected to lengthening contractions as before. At 7 days post-injury, soleus muscles from anti-P-selectin-treated mice contained 48% fewer mononuclear cells that bound endoplasmic reticulum-bone marrow-derived macrophage 1 (P=0.019), a marker for mature macrophages and dendritic cells, and 84% fewer fibers expressing developmental isoforms of myosin heavy chain (P =0.006), compared with muscles from isotype-injected, control mice. The number of CD11b⁺ cells was not significantly different between groups. The results are consistent with the concept that P-selectin is involved in the recruitment, maturation, and/or activation of cells that are critical for muscle fiber regeneration.

Key Words: macrophage • satellite cell • dendritic cell • myotube

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