title: Novel intracellular N-terminal truncated matrix metalloproteinase-2 isoform in skeletal muscle ischemia-reperfusion injury.
abstract: Ischemia-reperfusion injury (IRI) occurs when blood returns to tissues following a period of ischemia. Reintroduction of blood flow results in the production of free radicals and reactive oxygen species that damage cells. Skeletal muscle IRI is commonly seen in orthopedic trauma patients. Experimental studies in other organ systems have elucidated the importance of extracellular and intracellular matrix metalloproteinase-2 (MMP-2) isoforms in regulating tissue damage in the setting of oxidant stress resulting from IRI. Although the extracellular full-length isoform of MMP-2 (FL-MMP-2) has been previously studied in the setting of skeletal muscle IRI, studies investigating the role of the N-terminal truncated isoform (NTT-MMP-2) in this setting are lacking. In this study, we first demonstrated significant increases in FL- and NTT-MMP-2 gene expression in C2C12 myoblast cells responding to re-oxygenation following hypoxia in vitro. We then evaluated the expression of FL- and NTT-MMP-2 in modulating skeletal muscle IRI using a previously validated murine model. NTT-MMP-2, but not FL-MMP-2 expression was significantly increased in skeletal muscle following IRI. Moreover, the expression of toll-like receptors (TLRs) -2 and -4, IL-6, OAS-1A, and CXCL1 was also significantly up-regulated following IRI. Treatment with the potent anti-oxidant pyrrolidine dithiocarbamate (PDTC) significantly suppressed NTT-MMP-2, but not FL-MMP-2 expression and improved muscle viability following IRI. This data suggests that NTT-MMP-2, but not FL-MMP-2, is the major isoform of MMP-2 involved in skeletal muscle IRI.
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.|Department of Medicine, University of California, San Francisco, California.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Joshi
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lee
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.|Department of Medicine, University of California, San Francisco, California.
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Heejae
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.|Department of Orthopaedic Surgery, University of California, San Francisco, California.
authors.forename: Hubert T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.|Department of Medicine, University of California, San Francisco, California.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Delgado
authors.affiliation: Department of Veterans Affairs, San Francisco Veterans Affairs Medical Center, San Francisco, California.|Department of Orthopaedic Surgery, University of California, San Francisco, California.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D000860:Hypoxia / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply / Q000201:enzymology*; D015427:Reperfusion Injury / Q000201:enzymology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D007527:Isoenzymes; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: N-terminal truncated matrix metalloproteinase-2; hindlimb ischemia-reperfusion injury; hypoxia; matrix metalloproteinase-2; skeletal muscle