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1 Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, MO, USA
2 Department of Cell Biology and Histology, University of Nijmegen, Nijmegen, The Netherlands
3 Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, MO, USA; Biomedical Sciences, University of Missouri-Columbia, Columbia, MO, USA; Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, USA
* To whom correspondence should be addressed. E-mail: Terjungr{at}missouri.edu.
The production of AMP by adenylate kinase (AK) and subsequent deamination by AMP deaminase (AMPD) limits ADP accumulation during conditions of high-energy demand in skeletal muscle. The goal of this study was to investigate the consequences of adenylate kinase deficiency on adenine nucleotide management and whole muscle function at high-energy demands. To do this we examined isometric tetanic contractile performance of the gastrocnemius-plantaris-soleus (GPS) muscle group in situ in AK1-/- mice and WT controls over a range of contraction frequencies (30 to 120 tetani/min). We found that AK1-/- muscle exhibited a diminished IMP formation rate (14% of WT) and an inordinate accumulation of ADP (~1.5mM) at the highest energy demands, compared to WT controls. AK deficient muscle exhibited similar initial contractile performance (521±9 and 521±10 g tension in WT and AK1-/- muscle respectively) followed by a significant slowing of relaxation kinetics at the highest energy demands relative to WT controls. This is consistent with a depressed capacity to sequester calcium in the presence of high ADP. However, the overall pattern of fatigue in AK1-/- was similar to WT control muscle. Our findings directly demonstrate the importance of AMP formation and subsequent deamination in limiting ADP accumulation. Whole muscle contractile performance was however, remarkably tolerant of ADP accumulation markedly in excess of what normally occurs in skeletal muscle.
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