Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial dysfunction.DMD treatment includes support for mitochondrial function.The purp...Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial dysfunction.DMD treatment includes support for mitochondrial function.The purpose of this work was to evaluate the effects of the lipophilic cation MKT-077,capable of modulating mitochondrial activity,on the structure and function of cardiac mitochondria in mdx and wild-type mice,as well as the state of this organ.Methods:Animals were divided into 4 groups:wild type(WT),WT+5 mg/kg MKT-077,mdx,mdx+5 mg/kg MKT-077.MKT-077 was administered intraperitoneally daily for 28 days.Finally,we assessed the parameters of the functioning of the cardiac mitochondria of mice,the expression of genes encoding proteins involved in mitochondrial communication,as well as the histology and ultrastructure of the myocardium and heart rate.Results:MKT-077 was shown to reverse mitochondrial hyperfunctionalization in mdx mice,reducing respiratory parameters to WT levels.MKT-077 also inhibited mitochondrial respiration in the hearts of WT mice.MKT-077 administration was accompanied by a tendency to normalize calcium retention capacity in the cardiac mitochondria of mdx mice.Myocardial ultrastructure and gene signature of mdx+MKT077 animals demonstrated increased mitophagy.We noted changes in the sarcoplasmic reticulum(SR)/mitochondria contacts,accompanied by differential changes in the level of genes encoding proteins involved in the communication of these organelles.This effect of MKT-077 was accompanied by normalization of the relative heart weight of mdx mice,a decrease in the level of fibrosis,and a tendency toward normalization of heart rate.Conclusion:MKT-077-induced reversal of cardiac mitochondrial hyperfunctionalization in mdx mice may promote a healthy-like state of the myocardium in these animals.展开更多
基金supported by a grant from the Russian Science Foundation(23-75-10006).
文摘Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial dysfunction.DMD treatment includes support for mitochondrial function.The purpose of this work was to evaluate the effects of the lipophilic cation MKT-077,capable of modulating mitochondrial activity,on the structure and function of cardiac mitochondria in mdx and wild-type mice,as well as the state of this organ.Methods:Animals were divided into 4 groups:wild type(WT),WT+5 mg/kg MKT-077,mdx,mdx+5 mg/kg MKT-077.MKT-077 was administered intraperitoneally daily for 28 days.Finally,we assessed the parameters of the functioning of the cardiac mitochondria of mice,the expression of genes encoding proteins involved in mitochondrial communication,as well as the histology and ultrastructure of the myocardium and heart rate.Results:MKT-077 was shown to reverse mitochondrial hyperfunctionalization in mdx mice,reducing respiratory parameters to WT levels.MKT-077 also inhibited mitochondrial respiration in the hearts of WT mice.MKT-077 administration was accompanied by a tendency to normalize calcium retention capacity in the cardiac mitochondria of mdx mice.Myocardial ultrastructure and gene signature of mdx+MKT077 animals demonstrated increased mitophagy.We noted changes in the sarcoplasmic reticulum(SR)/mitochondria contacts,accompanied by differential changes in the level of genes encoding proteins involved in the communication of these organelles.This effect of MKT-077 was accompanied by normalization of the relative heart weight of mdx mice,a decrease in the level of fibrosis,and a tendency toward normalization of heart rate.Conclusion:MKT-077-induced reversal of cardiac mitochondrial hyperfunctionalization in mdx mice may promote a healthy-like state of the myocardium in these animals.
