title: Decline of Phosphotransfer and Substrate Supply Metabolic Circuits Hinders ATP Cycling in Aging Myocardium.
abstract: 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 Pi[18O], γ-ATP[18O], β-ADP[18O], and creatine phosphate CrP[18O] 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 G6P[18O] turnover with relatively constant glycogenolytic flux or G1P[18O] 18O-labeling. Labeling of G3P[18O], 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 Pi[18O] and a lower Pi[18O]/γ-ATP[18 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.
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Emirhan
authors.initials: E
authors.lastname: Nemutlu
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Anu
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Viqar
authors.affiliation: Center for Integrative Research on Cardiovascular Aging (CIRCA), Aurora University of Wisconsin Medical Group, Aurora Health Care, Milwaukee, Wisconsin, United States of America.
authors.forename: Ekhson
authors.initials: E
authors.lastname: Holmuhamedov
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.affiliation: Center for Integrative Research on Cardiovascular Aging (CIRCA), Aurora University of Wisconsin Medical Group, Aurora Health Care, Milwaukee, Wisconsin, United States of America.
authors.forename: Arshad
authors.initials: A
authors.lastname: Jahangir
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Petras
authors.initials: P
authors.lastname: Dzeja
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D006003:Glycogen / Q000378:metabolism; D006031:Glycosylation; D006325:Heart Atria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats
chemical_list: D000255:Adenosine Triphosphate; D006003:Glycogen