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. ß

Protective Effects of Honey, Apis mellifera Meda Skorikov, on Ischemia-Reperfusion Induced Muscle Injury

“…Ischemia is characterized by decrease in blood flow that is usually caused by disruption in oxygen and nutrients delivery to the tissues (Aksu et al, 2015). After systemic events that occur during ischemia such as impairment of energy production, toxic metabolites production and cell damage, a series of circumstances is started by reperfusion including free radicals generation, acute inflammatory responses, lipid peroxidation, protein and DNA damage and finally development of cell necrosis (Dong et al, 2014;Jalili et al, 2015;Joshi et al, 2016;Salahshoor et al, 2015Salahshoor et al, , 2016. It has been proved that free radicals especially reactive oxygen species (ROS) reactive nitrogen species (RNS) and inflammatory cells such as neutrophils are involved in the multifactorial pathophysiology of ischemia-reperfusion injury (IRI).…”