Metabolic Consequences in Adenine Nucleotides Caused by Adenylate Kinase (AK1-/-) Deficiency During Contractions

Abstract

2294 An energy deficit caused by intense muscle contractions leads to IMP accumulation due to net AMP production and subsequent AMP deamination. Adenylate kinase deficient muscle should exhibit a lack of IMP accumulation due to an impaired capacity for AMP production. This impairment, evident during intense contractions should be tempered during lower contraction intensities. PURPOSE: To examine the metabolic consequences of adenylate kinase deficiency in muscle during contractions of varying intensity. METHODS: Isometric tetanic contractions of varying intensity (120, 90, 60, and 30 per min) were elicited from adenylate kinase 1 knockout, (cytosolic isoform deficient, AK1−/−), and control (WT) mice by in situ stimulation. Gastrocnemius muscle was taken from both the contracted and rested muscles and analyzed for adenine nucleotides (ATP, ADP, AMP) and IMP after 20, 40, 60, and 120 contractions. RESULTS: The consequence of adenylate kinase deficiency was most evident at 120 tetani/min as seen by an IMP accumulation of 2.51 ± .34 vs. 0.43 ± .05 micromol/g wet weight in WT and AK1−/− muscles respectively. IMP accumulation was tempered at less intense contractions (30 tetani/min) in the WT mice (0.83 ± 0.06 micromol/g wet wt.), but still much greater than IMP accumulation in AK1−/− muscle (0.13 ± 0.03 micromol/g wet wt.). During conditions of high energy demand, adenylate kinase deficiency resulted in inordinate elevations in ADP that scaled with contraction intensity. CONCLUSIONS: Adenylate kinase deficient muscle exhibits a metabolic imbalance during conditions of high energy demand where ATP is not cleared to IMP. The resultant elevation in ADP and modified AMP accumulation are what makes this mouse model a resource to study the effects of an exaggerated change in energy state, and metabolic processes responsive to adenylate metabolites. Supported by NIH grant AR 21617