Rearrangement of energetic and substrate utilization networks compensate for chronic myocardial creatine kinase deficiency

Petras P Dzeja, Kirsten Hoyer, Rong Tian, Song Zhang, Emirhan Nemutlu, Matthias Spindler, Joanne S. Ingwall

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37 Scopus citations

Abstract

Plasticity of the cellular bioenergetic system is fundamental to every organ function, stress adaptation and disease tolerance. Here, remodelling of phosphotransfer and substrate utilization networks in response to chronic creatine kinase (CK) deficiency, a hallmark of cardiovascular disease, has been revealed in transgenic mouse models lacking either cytosolic M-CK (M-CK -/-) or both M-CK and sarcomeric mitochondrial CK (M-CK/ScCKmit -/-) isoforms. The dynamic metabolomic signatures of these adaptations have also been defined. Tracking perturbations in metabolic dynamics with 18O and 13C isotopes and 31P NMR and mass spectrometry demonstrate that hearts lacking M-CK have lower phosphocreatine (PCr) turnover but increased glucose-6-phosphate (G-6-P) turnover, glucose utilization and inorganic phosphate compartmentation with normal ATP γ-phosphoryl dynamics. Hearts lacking both M-CK and sarcomeric mitochondrial CK have diminished PCr turnover, total phosphotransfer capacity and intracellular energetic communication but increased dynamics of β-phosphoryls of ADP/ATP, G-6-P and γ-/β-phosphoryls of GTP, indicating redistribution of flux through adenylate kinase (AK), glycolytic and guanine nucleotide phosphotransfer circuits. Higher glycolytic and mitochondrial capacities and increased glucose tolerance contributed to metabolic resilience of M-CK/ScCKmit -/- mice. Multivariate analysis revealed unique metabolomic signatures for M-CK -/- and M-CK/ScCKmit -/- hearts suggesting that rearrangements in phosphotransfer and substrate utilization networks provide compensation for genetic CK deficiency. This new information highlights the significance of integrated CK-, AK-, guanine nucleotide- and glycolytic enzyme-catalysed phosphotransfer networks in supporting the adaptivity and robustness of the cellular energetic system.

Original languageEnglish (US)
Pages (from-to)5193-5211
Number of pages19
JournalJournal of Physiology
Volume589
Issue number21
DOIs
StatePublished - Nov 2011

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ASJC Scopus subject areas

  • Physiology

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