Li Sheng,Wang Zhi,Yao Jing Wen,Jiao Hong Chao,Wang Xiao Juan,Lin Hai,Zhao Jing Peng
To uncover the molecular mechanism underlying glucocorticoid-induced loss of mitochondrial integrity in skeletal muscles, studies were performed to investigate whether the peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1)-mediated pathway was involved in this process. In an in vivo trial, 3 groups of 30-d-old Arbor Acres male broilers were randomly subjected to one of the following treatments for 7 days: corticosterone (CORT, 30 mg/kg diet), control (blank), and pair-feeding (restricted to the same feed intake as for the CORT treatment), each with 6 replicates of 15 birds. Mitochondrial abundance, morphology, and function were determined in the pectoralis major and biceps femoris muscles. In an in vitro trial, a primary culture of embryonic chick myotubes was incubated with a serum-free medium for 24 h in the presence or absence of CORT (0, 200, and 1,000 nM). Results showed that CORT destroyed mitochondrial ultrastructure (p < 0.01), and decreased the enzymatic activity and protein expression of respiratory chain complexes (p < 0.05), leading to an inferior coupling efficiency (p < 0.05). As reflected by a decline in mitochondrial density (p < 0.01) and mitochondrial DNA copy number (p < 0.05), CORT reduced mitochondrial contents. Among all three PGC-1 family members, only PGC-1β was down-regulated by CORT at the protein level (p < 0.05). Some aspects of these responses were tissue-specific and seemed to result from the depressed feed intake. Overall, CORT may impair mitochondrial biogenesis and oxidative phosphorylation in a PGC-1β-dependent manner in chicken muscles.
Postmenopausal osteoporosis (PMOP) is linked to iron accumulation. Melatonin has iron-chelating and antioxidant properties, but its mechanism against osteoclastogenesis remains unclear. This study investigated whether melatonin suppresses osteoclast formation by targeting the iron/ROS-CREB-PGC-1β-mediated mitochondrial biogenesis pathway. In vitro , bone marrow-derived macrophages (BMMs) were treated with RANKL and melatonin (10–1000 nM). Melatonin concentration-dependently inhibited osteoclast differentiation, reduced intracellular ferrous and total iron levels, decreased ROS and oxidative stress markers, and suppressed mitochondrial biogenesis. Mechanistically, melatonin indirectly suppressed PGC‑1β expression via inhibition of CREB phosphorylation, without affecting PGC‑1α expression. The CREB activator forskolin reversed melatonin's effects, whereas the CREB inhibitor 666-15 mimicked them. In vivo , ovariectomized (OVX) mice received weekly injections of iron dextran to model moderate iron overload, with or without oral melatonin. Melatonin ameliorated iron‑induced bone loss, improved bone microarchitecture and biomechanical properties, reduced tissue iron stores and bone ROS levels, and suppressed osteoclast mitochondrial biogenesis and the CREB/PGC-1β pathway; these effects were counteracted by forskolin. In conclusion, melatonin prevents osteoclastogenesis and counters bone loss due to iron accumulation in estrogen‑deficient conditions by chelating iron, scavenging ROS, and blocking the iron/ROS‑activated CREB/PGC‑1β axis, thereby suppressing mitochondrial biogenesis. This study offers a mechanistic explanation for using melatonin as a possible treatment for PMOP, particularly when accompanied by iron overload.
To explore effective therapeutic strategy on nonalcoholic fatty liver disease (NAFLD), the amphiphilic oligochitosan derivative containing ursodeoxycholic acid (UDCA) was synthesized and named as UBC, which could self-assemble and encapsulate exenatide (Exe) to obtain Exe-UBC nano-vesicle. Exe-UBC could be uptaken by fatty-acid cultured cells and release UDCA and Exe responsive to the high esterase concentration. In vitro experiments demonstrated that Exe-UBC activated the expression level of SIRT1 with inhibited expression of PGC-1β and PPAR-γ and consequently exerted synergistic bioaction immediately on reducing lipidosis. After a month of Exe-UBC treated through intravenous injection, the body weight of high-fat diet feeding C57BL/6 mice recovered to ordinary level, and their lipid contents in the liver declined significantly. The recovery in hepatic function indexes like TG , AST , and ALT further revealed the superiority of Exe-UBC vesicles. These results suggested that the co-delivery of UDCA and Exe via Exe-UBC could be a potent platform for NAFLD treatment.
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