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.
Highlights
Vigorous atrial function is critical for sustaining normal heart work and uninterrupted blood flow yet it declines with aging increasing susceptibility to atrial fibrillation (AF) [1,2]
New evidence has accumulated that phosphotransfer circuits composed from creatine kinase (CK), adenylate kinase (AK), and glycolytic/glycogenolytic enzymes along with substrate shuttles, such as glycerol-3-phosphate (G3P), are essential parts of the cardiac bioenergetic infrastructure integral to maintaining energy homeostasis [11,13,14,15,16,17]
Enzyme activities of CK and AK tightly correlated with ATP concentration and AF duration, implying that impairment in atrial bioenergetics may contribute to the substrate for AF [7,18,34]
Summary
Vigorous atrial function is critical for sustaining normal heart work and uninterrupted blood flow yet it declines with aging increasing susceptibility to atrial fibrillation (AF) [1,2]. The failing ventricle myocardium is characterized by reduction of high-energy phosphates and lower activity of the phosphotransfer enzymes CK and AK which facilitate transfer of high-energy phosphoryls and their metabolites from sites of production to sites of utilization [7,9,10,18,19,20]. These phosphotransfer systems serve as metabolic signal transducers, coupling the cell energetic status to ion channel function and membrane excitability [21,22,23,24]. The significance of changes in metabolic flux through atrial phosphotransfer systems in aging myocardium has not been determined
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