Effects Of Methionine Restriction On Heart And Kidney Function In Middle-aged Mice With High Energy Diets

Obesity and aging have become public health issues worldwide.It has gradually become a hot issue in the field of nutrition at home and abroad how to improve the heart and kidney function damage caused by obesity and aging.Oxidative stress and inflammatory responses are the main factors that cause obesity and senile impaired heart and kidney function.Studies have shown that methionine restriction（MR）can enhance energy metabolism and reduce oxidative stress as well as inflammation in the body and inhibit age-related diseases occur.Endogenous hydrogen sulfide（H₂S）has a certain protective effect in the cardiovascular system and is closely related to the maintenance of renal function.MR can promote the generation of endogenous H₂S by regulating the TSP pathway.This article aims to explore the effects of different MR levels on heart and kidney function in middle-aged and elderly mice with different energy intake levels,and explore possible mechanisms around the synthesis of endogenous H₂S and the regulation of TSP in heart and kidney tissues.After 80 week-old male C57BL/6J mice were adaptively fed for 1 week,all mice were randomly divided into 6 experimental groups according to body weight:（1）low fat+normal methionine diet group（CON,0.86%methionine+4%fat）;（2）low fat+40%methionine restricted diet group（CMR40,0.52%methionine+4%fat）;（3）low fat+80%methionine restricted diet group（CMR80,0.17%methionine+4%Fat）;（4）high fat+normal methionine diet group（HF,0.86%methionine+24%fat）;（5）high fat+40%methionine restricted diet group（HMR40,0.52%methionine+24%fat）;（6）high fat+80%methionine restricted diet group（HMR80,0.17%methionine+24%fat）.The whole experiment lasted for 15 weeks.At the 14th week,the CLAMS comprehensive experimental animal monitoring system was used to determine the feed intake and basal metabolic indexes.At the end of the breeding cycle,the mice were tested for echocardiography and blood pressure levels before sampling.80%MR can increase energy expenditure and autonomic activity in normal and high-fat diet mice,and reduce body weight and body fat content.80%MR reduced TG,TC and LDL-C content in plasma and increased HDL-C content in mice.40%MR did not significantly change the body weight,energy expenditure and lipid metabolism of mice.After different levels of MR intervention,the blood pressure of mice was maintained at normal levels.In cardiac tissue:80%MR improved cardiac systolic dysfunction in middle-aged and obese mice,and maintained normal myocardial cell tissue structure;up-regulation of genes in the antioxidant defense system reduced plasma and myocardial oxidative stress,and improved inflammatory response;up-regulated cardiac Bcl-2,down-regulated Bax mRNA and protein expression,improved myocardial cell apoptosis;activated AMPK/SIRT1-PGC-1αsignaling pathway,enhanced myocardial ATP production,increased ATPase activity and improves myocardial energy metabolism.80%MR up-regulated the mRNA expression of cardiac CBS and CSE genes and increased cardiac H₂S production,and up-regulated cardiac MTHFR and Mtr mRNA expression,improved the remethylation pathway of Hcy.The 40%MR under normal diet was not different from that in the CON group.The trend of 40%MR and 80%MR under the high-fat diet was the same but not significant.In kidney tissue:80%MR improved kidney metabolism and reduce urinary protein in middle-aged mice with normal and high-fat diets;improved abnormal renal tissue structure caused by high-fat diets;up-regulated genes of the antioxidant defense system to reduce renal oxidative stress,It also improved the inflammatory response of the kidney;up-regulated the mRNA expression of CBS and CSE in the kidney and increased the production of renal H₂S;80%MR increased the plasma and kidney adiponectin levels in normal and high-fat diet mice,and up-regulated the mRNA expression of AdipoR1 to protect kidney function by activating renal AMPK/mTOR signaling pathway.The trend of 40%MR and 80%MR was the same but not significant.The results show that MR may increase the endogenous H₂S production in the heart and kidney tissues of middle-aged and elderly mice,thereby improving the oxidative stress and inflammatory response of the heart and kidney tissues,reducing animal weight,and improving abnormal lipid metabolism.At the same time,by activating theAMPK/SIRT1-PGC-1αsignaling pathway,the energy metabolism of the heart was enhancedand the cardiac contraction function was improved.In addition,increasing plasma and renal adiponectin levels and up-regulating AdipoR1 expression activate renal AMPK/mTOR signaling pathways to protect renal function.