Kolonics 2023 MiP2023

Accelerated epigenetic changes may contribute to the development of metabolic syndrome revealed by NADH FLIM

Link: MiP2023 Obergurgl AT

Kolonics Attila (2023)

Event: MiP2023 Obergurgl AT

Authors:Kolonics Attila, Kawamura T, Szipoecs R, Radak Z

Aging leads to a loss of muscle mass and a decline in skeletal muscle function (1) leading to imbalance between glucose and lipid metabolism (2). Low exercise capacity is highly correlated with skeletal muscle dysfunction and metabolic disorders (3). Age-associated factors intrinsic to the muscle, including defects in NAD+ synthesis (4), reduced mitochondrial copy number (5), and epigenomic changes affecting the expression of metabolic genes (6) reported. We aimed to characterize mitochondrial fitness of liver in an inborn low- versus high-capacity runners (LCR/HCR) aged female rats to study the spread of metabolic dysfunction. LCR/HCR rats (44th generation, 24 months old) used were artificially selected from genetically heterogeneous N:NIH stock (7). NAD(P)H lifetime imaging (FLIM) characterized liver metabolism in frozen tissues; basal and succinate induced ROS production was evaluated by Amplex Red in the presence of horseradish peroxidase, ΔΨmt by TMRE in intact liver mitochondria. HCR group was less vulnerable to metabolic disorder comparing to LCR group proofed by decreased body mass and increased VO2max. It was further supported by mitochondrial analysis of intact liver mitochondria. Basal ROS production showed no difference between LCR and HCR groups although succinate induced ROS production was higher in LCR group at identical ΔΨmt. NAD(P)H FLIM uncovered subtle alterations: LCR groups had significantly less free NADH comparing to HCR groups (Fig.1). In conclusion, epigenetic changes induced decline of metabolism correlated with deterioration of liver mitochondrial fitness. Succinate induced ROS-production at same membrane potential negatively correlated with free NADH-level. 1. Frontera WR, Hughes VA, Lutz KJ, Evans WJ (1985) A cross-sectional study of muscle strength and mass in 45- to 78-yr-old men and women. J Appl Physiol. 1991 Aug;71(2):644-50 http://doi.org/10.1152/jappl.1991.71.2.644 2. Gheller BJ, Riddle ES, Lem MR, Thalacker-Mercer AE (2016) Understanding Age-Related Changes in Skeletal Muscle Metabolism: Differences Between Females and Males. Annu Rev Nutr. 2016 Jul 17;36:129-56 http://doi.org/10.1146/annurev-nutr-071715-050901 3. Biolo G, Cederholm T, Muscaritoli M (2014) Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia. Clin Nutr. 2014 Oct;33(5):737-48 http://doi.org/10.1016/j.clnu.2014.03.007 4. Yoshino J, Mills KF, Yoon MJ, Imai S (2011) Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011 Oct 5;14(4):528-36 http://doi.org/10.1016/j.cmet.2011.08.014 5. Barazzoni R, Short KR, Nair KS (2000) Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver, and heart. J Biol Chem. 2000 Feb4; 275(5): 3343-7 http://doi.org/10.1074/jbc.275.5.3343 6. Jiang MH, Fei J, Lan MS, Lu ZP, Liu M, Fan WW, Gao X, Lu DR (2008) Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential. Diabetologia. 2008 Aug;51(8):1525-33 http://doi.org/10.1007/s00125-008-1034-8 7. Koch LG, Britton SL (2007) Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol Genomics. 2001 Feb 7;5(1):45-52 http://doi.org/10.1152/physiolgenomics.2001.5.1.45

Labels: Pathology: Aging;senescence 

Organism: Rat  Tissue;cell: Liver 

Event: E2