Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis

Abstract

This study aimed to investigate whether inhibition of autophagy and endoplasmic reticulum (ER stress) associates with the antifibrogenic effect of melatonin in mice treated with carbon tetrachloride (CCl4 ). Mice received CCl4 5 μL/g body wt i.p. twice a week for 4 wk or 6 wk. Melatonin was given at 5 or 10 mg/kg/day i.p, beginning 2 wk after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of α-smooth muscle actin (α-SMA)-positive cells. CCl4 induced an autophagic response measured as the presence of autophagic vesicles, protein 1 light chain 3 (LC3) staining, conversion of LC3-I to autophagosome-associated LC3-II, changes in expression of beclin-1, UV radiation resistance-associated gene (UVRAG), ubiquitin-like autophagy-related (Atg5), Atg12, Atg16L1, sequestosome 1 (p62/SQSTM1), and lysosome-associated membrane protein (LAMP)-2, and increased phosphorylation of the mammalian target of rapamycin (mTOR). There was an increase in the expression of the ER stress chaperones CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin-heavy-chain-binding protein (BiP/GRP78), and 94-kDa glucose-regulated protein (GRP94), and in the mRNA levels of pancreatic ER kinase (PERK), activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), and spliced X-box-binding protein-1 (XBP1). Phospho-IRE1, ATF6, and phospho-PERK protein concentration also increased significantly. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cells activation by melatonin. Furthermore, treatment with the indole resulted in significant inhibition of the autophagic flux and the unfolded protein response. Findings from this study give new insight into molecular pathways accounting for the protective effect of melatonin in fibrogenesis.

Melatonin as a Potential Agent in the Treatment of Sarcopenia

“…In relation to muscle, melatonin is highly versatile molecule and either induces autophagy [86] or inhibits it [87], depending on pathological processes involved, since oxidative stress has a close relationship with autophagy. For example, melatonin induces autophagy in myoblast cells collaborating in myogenic differentiation (MyoD) degradation [88] but it inhibits autophagy in muscles from carbon tetrachloride-treated mice by reducing oxidative stress-induced damage [89]. …”

“…Melatonin reduces endoplasmic reticulum stress in skeletal muscle by increasing the expression of several proteins as well as mRNA levels [89]; this improves protein synthesis. Likewise, melatonin is an important regulator of proteasome [94] and lysosomal mechanisms [88], thereby enhancing cell quality.…”

Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats

“…Recently, increasing studies show ER stress is a salient feature of numerous liver diseases [16,17]. Recently, melatonin is shown to be effective in reducing ER stress-induced hepatic steatosis [18] and tetrachloride-induced liver fibrosis [19]. …”

Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway

“…Yoo and Jeung showed that melatonin suppresses CsA-mediated autophagy in rat pituitary GH3 cells [18]. San-Miguel et al demonstrated that melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis [19].…”

“…The effect of melatonin on autophagy has been investigated more recently [18][19][20]. Yoo and Jeung showed that melatonin suppresses CsA-mediated autophagy in rat pituitary GH3 cells [18].…”