Effect of time-restricted feeding on myocardial injury and its regulatory effect on FGF21 level in serum and myocardial tissues in mice with heart failure with preserved ejection fraction
Objective To observe the effects of time-restricted feeding(TRF)on cardiac dysfunction,myocardial remodeling,myocardial mitochondrial structure and function,myocardial oxidative stress response,and myocardial energy metabolism in mice with heart failure with preserved ejection fraction(HFpEF),and to investigate the regulatory role of TRF on the levels of fibroblast growth factor 21(FGF21)in serum and myocardial tissues,in order to explore the role and mechanism of TRF in ameliorating myocardial injury in HFpEF.Methods Thirty FGF21 knockout(Fgf21-/-)mice were divided into the Fgf21-/-+ALb group and Fgf21-/-+TRF group.Thirty wild-type(WT)mice were divided into the WT+ALb group and WT+TRF group.Mice in all the four groups were fed a 60%high-fat diet,and Nω-nitro-L-arginine methyl ester hydrochloride(L-NAME,0.5 g/L)was added to daily drinking water to establish the HFpEF models.Mice in the WT+TRF group and Fgf21-/-+TRF group underwent TRF,with feeding allowed from 21:00 to 05:00 the next day and fasting during the rest of the time.Mice in the WT+ALb group and Fgf21-/-+ALb group had access to food 24 h a day.After 8 weeks,the myocardial injury-related indicators were observed,including cardiac function(LVEF,E/A,E/E',BNP),myocardial remodeling(HW/TL,mean cross-sectional area of cardiomyocyte,myocardial collagen deposition,and the mRNA levels of fibrosis-related genes Col1a1,Col3a1,Fn1,and CTGF),myocardial mitochondrial structure and function(damaged mitochondria ratio,ATP production,myocardial ATP content,Complex I activity,Complex V activity),myo-cardial oxidative stress levels(ROS production,SOD activity,MDA content),myocardial energy metabolism(protein ex-pression levels of CD36,CPT1b,the percentage of 13C Ac-CoA,and the mRNA levels of glucose metabolism-related genes Glut1,Glut4,PFK1),as well as FGF21 expression levels in serum and myocardial tissues.Results After 8 weeks of feeding,compared with the WT+ALb group,the E/A,E/E'values and serum BNP level decreased(all P<0.01),heart weight,HW/TL value and mean cross-sectional area of cardiomyocyte decreased(all P<0.01),the collagen deposition and the mRNA expression levels of Col1a1,Col3a1,Fn1,CTGF decreased(all P<0.01),the proportion of damaged mito-chondria decreased,mitochondrial ATP production and activities of mitochondrial complex Ⅰ and Ⅴ increased(all P<0.01),myocardial ROS production and MDA content decreased,SOD activity increased(all P<0.01),the protein ex-pression levels of CD36 and CPT1b increased,the percentage of 13C Ac-CoA increased(all P<0.01),the mRNA expres-sion levels of Glut1,Glut4 and PFK1 decreased(all P<0.01),and the serum FGF21 level and the myocardial FGF21 pro-tein and mRNA expression levels increased in the WT+TRF group(all P<0.01).Compared with the WT+TRF group,the E/A,E/E'values and serum BNP levels increased(all P<0.01),heart weight,HW/TL value and mean cross-sectional area of cardiomyocyte increased(all P<0.01),the collagen deposition and mRNA expression levels of Col1a1,Col3a1,Fn1,CTGF increased(all P<0.01),the proportion of damaged mitochondria increased,mitochondrial ATP production and the activities of mitochondrial complex Ⅰ and Ⅴ decreased(all P<0.01),myocardial ROS production and MDA con-tent increased,SOD activity decreased(all P<0.01),the protein expression levels of CD36 and CPT1b decreased,the percentage of 13C Ac-CoA decreased(all P<0.01),and the mRNA expression levels of Glut1,Glut4 and PFK1 increased in Fgf21-/-+TRF group(all P<0.01).Conclusions TRF has beneficial effects on cardiac function,myocardial remodel-ing,myocardial mitochondrial structure and function,myocardial oxidative stress response,and myocardial energy metabo-lism in mice with HFpEF.Additionally,it promotes the expression of FGF21.By elevating the expression level of FGF21,TRF can enhance myocardial fatty acid metabolism,improve myocardial mitochondrial structural and function,and inhibit oxidative stress levels,thereby ameliorating cardiac dysfunction and myocardial remodeling in HFpEF mice,and ultimate-ly mitigating myocardial injury.
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