MG53 anchored by dysferlin to cell membrane reduces hepatocyte apoptosis which induced by ischaemia/reperfusion injury in vivo and in vitro

Abstract

Hepatic ischaemia/reperfusion (HIR) induces severe damage on hepatocyte cell membrane, which leads to hepatocyte death and the subsequent HIR injury. In this study, we investigated the role and the mechanism of mitsugumin‐53 (MG53), a novel cell membrane repair protein, in protecting the liver against HIR injury. Rats were subjected to sham operation or 70% warm HIR with or without recombined MG53 (rhMG53), caudal vein‐injected 2 hrs before inducing HIR. In vitro, cultured hepatocyte AML12 cells were subjected to hypoxia/reoxygenation (H/R) in the presence of rhMG53 and/or dysferlin gene shRNAs or adenovirus transfection. HIR resulted in severe liver injury manifested as severe liver histological changes and increased AST and ALT release. Post‐ischaemic hepatic oxidative stress was significantly enhanced demonstrated by elevated dihydroethidium level, increased 4‐hydroxynonenal, enhanced 15‐F2t‐isoprostane and decreased SOD activity. rhMG53 administration attenuated post‐HIR liver injury, decreased liver oxidative stress and further enhanced dysferlin protein expression and its colocalization with MG53. Similarly, H/R induced AML12 cell injury and oxidative stress, which were abolished by either rhMG53 or dysferlin overexpression but were exacerbated by dysferlin gene knockdown. Dysferlin overexpression further increased H/R‐induced increased colocalization of MG53 and dysferlin. In conclusion, MG53 was anchored by dysferlin to reduce oxidative stress and cell death and attenuate HIR injury.

Enhancing membrane repair increases regeneration in a sciatic injury model

“…TRIM72/MG53 expression has been shown in lung type II alveolar epithelial cells where it is important for resisting mechanical injury to the lung [7]. While the liver does not usually express TRIM72/MG53, it appears that ischemia can induce expression in this tissue [22]. Thus, we conducted studies to determine if TRIM72/MG53 was expressed in neurons.…”

“…Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in multiple cell types, including striated muscle, liver, and alveolar epithelial cells [4][5][6][20][21][22]. TRIM72/MG53 is an essential component of the membrane repair machinery as TRIM72/MG53 ablation results in defective membrane repair, progressive skeletal myopathy, and vulnerability to ischemia-reperfusion injury (5,20).…”

“…Mice subjected to acute kidney injury showed decreased effects from ischemia reperfusion injury when treated with rhMG53 [8]. Interestingly, rhMG53 has been very successful in treating ischemia/reperfusion injury and has been also used in the treatment of skeletal muscle [25,26], cardiac muscle [27], and liver tissue [22]. Also, aerosolized rhMG53 has ameliorated the effects of ventilator-induced lung injury [7,28].…”

Identification of potential mechanism and hub genes for neuropathic pain by expression‐based genome‐wide association study

“…The protein expressions of CCL2, JUN, and CTSS were determined by Western blot analysis as previously described 27 with the use of the following antibodies: CCL2 (rabbit, 1:1000, Novus, Littleton, CO), JUN (rabbit, 1:1000, Novus), CTSS (rabbit, 1:2000, Novus) and GAPDH (rabbit, 1:1000, Novus). The protein expressions of CCL2, JUN, and CTSS were determined by Western blot analysis as previously described 27 with the use of the following antibodies: CCL2 (rabbit, 1:1000, Novus, Littleton, CO), JUN (rabbit, 1:1000, Novus), CTSS (rabbit, 1:2000, Novus) and GAPDH (rabbit, 1:1000, Novus).…”

Effects of Contusion and Exhaustive Exercise on Mg53, PTRF in Skeletal Muscle of Rats

“…In the present study, mitsugumin-53 (MG53) as a muscle-specific TRIM family protein(TRIM72), is an important component for regulating membrane repair and to be protective against cardiac Ischemia/reperfusion(I-R) and various forms of skeletal muscle injury. [1][2][3][4] MG53 is rapidly recruited to the injury site, and interacts with caveolin-3 to repair membrane damage. Mice lacking MG53 are easily damaged by exercise, and develop a progressive myopathy with atrophy.…”