AIM:This study aimed to investigate the mechanisms by which treadmill exercise ameliorates de-pressive-like behaviors and hippocampal neuronal damage in chronic restraint stress(CRS)mice by regulating mitophagy via the Sirt1/PGC-1α signaling axis.METHODS:Forty C57BL/6J mice were randomly assigned to control,CRS,CRS+exercise(EXE)and EXE groups(n=10).The mice in CRS and CRS+EXE groups underwent 4 h of daily restraint for 28 consecutive days to establish a depression model.The mice in CRS+EXE and EXE groups received 8 weeks of treadmill training(6 sessions per week).Depressive-like behaviors were evaluated using the open field test,sucrose preference test,and tail suspension test.Hippocampal neuronal morphology and pathological changes were examined using hematoxy-lin-eosin and Nissl staining,while neuronal apoptosis was assessed through TUNEL staining.Mitochondrial ultrastructure was examined via transmission electron microscopy.Mitochondrial membrane potential and ATP content were measured using JC-1 assay and ATP assay kits,respectively.The expression levels of silent information regulator 1(Sirt1),peroxi-some proliferator-activated receptor γ coactivator-1α(PGC-1α),PTEN-induced kinase 1(PINK1)and parkin were as-sessed at both mRNA and protein levels by RT-qPCR and Western blot assays,as well as key markers of mitophagy[mi-crotubule-associated protein 1 light chain 3(LC3)and P62]and apoptosis(cleaved caspase-9 and cleaved caspase-3).RESULTS:Compared with control group,CRS mice exhibited significantly reduced central zone entries and time(P<0.01),decreased sucrose preference(P<0.01),increased immobility time(P<0.01),severe hippocampal neuronal damage,elevated apoptosis rate(P<0.01),mitochondrial deterioration;reduced membrane potential and ATP content(P<0.01),decreased mRNA expressions of Sirt1,PGC-1α,PINK1,and parkin(P<0.01),reduced protein levels of Sirt1,PGC-1α,PINK1,parkin and LC3(P<0.01),and increased expression of P62,cleaved caspase-9,and cleaved caspase-3(P<0.01).The mice in CRS+EXE group showed significant improvements in all these parameters compared to CRS group(P<0.05 or P<0.01).CONCLUSION:Treadmill exercise mitigates CRS-induced depressive-like behaviors,mi-tochondrial dysfunction,and neuronal apoptosis in mice by activating the hippocampal Sirt1/PGC-1α/mitophagy axis.

AIM:This study aimed to investigate the mechanisms by which treadmill exercise ameliorates de-pressive-like behaviors and hippocampal neuronal damage in chronic restraint stress(CRS)mice by regulating mitophagy via the Sirt1/PGC-1α signaling axis.METHODS:Forty C57BL/6J mice were randomly assigned to control,CRS,CRS+exercise(EXE)and EXE groups(n=10).The mice in CRS and CRS+EXE groups underwent 4 h of daily restraint for 28 consecutive days to establish a depression model.The mice in CRS+EXE and EXE groups received 8 weeks of treadmill training(6 sessions per week).Depressive-like behaviors were evaluated using the open field test,sucrose preference test,and tail suspension test.Hippocampal neuronal morphology and pathological changes were examined using hematoxy-lin-eosin and Nissl staining,while neuronal apoptosis was assessed through TUNEL staining.Mitochondrial ultrastructure was examined via transmission electron microscopy.Mitochondrial membrane potential and ATP content were measured using JC-1 assay and ATP assay kits,respectively.The expression levels of silent information regulator 1(Sirt1),peroxi-some proliferator-activated receptor γ coactivator-1α(PGC-1α),PTEN-induced kinase 1(PINK1)and parkin were as-sessed at both mRNA and protein levels by RT-qPCR and Western blot assays,as well as key markers of mitophagy[mi-crotubule-associated protein 1 light chain 3(LC3)and P62]and apoptosis(cleaved caspase-9 and cleaved caspase-3).RESULTS:Compared with control group,CRS mice exhibited significantly reduced central zone entries and time(P<0.01),decreased sucrose preference(P<0.01),increased immobility time(P<0.01),severe hippocampal neuronal damage,elevated apoptosis rate(P<0.01),mitochondrial deterioration;reduced membrane potential and ATP content(P<0.01),decreased mRNA expressions of Sirt1,PGC-1α,PINK1,and parkin(P<0.01),reduced protein levels of Sirt1,PGC-1α,PINK1,parkin and LC3(P<0.01),and increased expression of P62,cleaved caspase-9,and cleaved caspase-3(P<0.01).The mice in CRS+EXE group showed significant improvements in all these parameters compared to CRS group(P<0.05 or P<0.01).CONCLUSION:Treadmill exercise mitigates CRS-induced depressive-like behaviors,mi-tochondrial dysfunction,and neuronal apoptosis in mice by activating the hippocampal Sirt1/PGC-1α/mitophagy axis.