Roles of ADAM8 in elimination of injured muscle fibers prior to skeletal muscle regeneration.

Skeletal muscle regeneration requires processes different from developmental myogenesis. One important difference is a requirement of inflammatory reactions prior to regenerative myogenesis, by which injured muscle fibers must be eliminated to make new myotubes. In this study, we show that efficient elimination of injured muscle fibers during regeneration requires ADAM8, a member of a disintegrin and metalloprotease (ADAM) family. Skeletal muscle of dystrophin-null mice, an animal model for Duchenne Muscular Dystrophy, deteriorates by the lack of ADAM8, which is characterized by increased area of muscle degeneration and increased number of necrotic and calcified muscle fibers. Adam8 is highly expressed in neutrophils. Upon cardiotoxin-induced skeletal muscle injury, neutrophils invade into muscle fibers through the basement membrane and form large clusters in wild type, but not in ADAM8-deficient mice, although neutrophils of the latter infiltrate into interstitial tissues similarly to those of wild type mice. Neutrophils lose their adhesiveness to blood vessels after infiltration, which includes an ectodomain shedding of P-Selectin Glycoprotein Ligand-1 (PSGL-1) on their surface. Expression of PSGL-1 on the surface of neutrophils remains higher in ADAM8-deficient than in wild type mice. These results suggest that ADAM8 mediates an enhanced invasiveness of neutrophils into injured muscle fibers by the removal of their adhesiveness to blood vessels after infiltration into interstitial tissues.