Decline of Phosphotransfer and Substrate Supply Metabolic Circuits Hinders ATP Cycling in Aging MyocardiumReport as inadecuate

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Integration of mitochondria with cytosolic ATP-consuming-ATP-sensing and substrate supply processes is critical for muscle bioenergetics and electrical activity. Whether age-dependent muscle weakness and increased electrical instability depends on perturbations in cellular energetic circuits is unknown. To define energetic remodeling of aged atrial myocardium we tracked dynamics of ATP synthesis-utilization, substrate supply, and phosphotransfer circuits through adenylate kinase AK, creatine kinase CK, and glycolytic-glycogenolytic pathways using 18O stable isotope-based phosphometabolomic technology. Samples of intact atrial myocardium from adult and aged rats were subjected to 18O-labeling procedure at resting basal state, and analyzed using the 18O-assisted HPLC-GC-MS technique. Characteristics for aging atria were lower inorganic phosphate Pi18O, γ-ATP18O, β-ADP18O, and creatine phosphate CrP18O 18O-labeling rates indicating diminished ATP utilization-synthesis and AK and CK phosphotransfer fluxes. Shift in dynamics of glycolytic phosphotransfer was reflected in the diminished G6P18O turnover with relatively constant glycogenolytic flux or G1P18O 18O-labeling. Labeling of G3P18O, an indicator of G3P-shuttle activity and substrate supply to mitochondria, was depressed in aged myocardium. Aged atrial myocardium displayed reduced incorporation of 18O into second 18O2, third 18O3, and fourth 18O4 positions of Pi18O and a lower Pi18O-γ-ATP18 O-labeling ratio, indicating delayed energetic communication and ATP cycling between mitochondria and cellular ATPases. Adrenergic stress alleviated diminished CK flux, AK catalyzed β-ATP turnover and energetic communication in aging atria. Thus, 18O-assisted phosphometabolomics uncovered simultaneous phosphotransfer through AK, CK, and glycolytic pathways and G3P substrate shuttle deficits hindering energetic communication and ATP cycling, which may underlie energetic vulnerability of aging atrial myocardium.

Author: Emirhan Nemutlu, Anu Gupta, Song Zhang, Maria Viqar, Ekhson Holmuhamedov, Andre Terzic, Arshad Jahangir , Petras Dzeja



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