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1 Medical Pharmacology and P hysiology, College of Medicine, University of Missouri-Columbia, Columbia, MO, USA
2 Department of Physiology, Michigan State University, East Lansing, MI, USA
3 Department of Physiology, Michigan State University, East Lansing, MI, USA; Department of Radiology, Michigan State University, East Lansing, MI, USA
4 Medical Pharmacology and P hysiology, College of Medicine, University of Missouri-Columbia, Columbia, MO, USA; Biomedical Sciences, College of Veterinary Medicine, 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.
Metabolic control within skeletal muscle is designed to limit ADP accumulation even during conditions where ATP demand is out of balance with ATP synthesis. This is accomplished by the reactions of adenylate kinase (AK; ADP+ADP
AMP+ATP) and AMP deaminase (AMPD; AMP+H2O
NH3+IMP), which limit ADP accumulation under these conditions. The purpose of this study was to determine if AK deficiency would result in sufficient ADP accumulation to be visible using 31P-NMRS during the high energy demands of frequent in situ tetanic contractions. To do this we examined the high energy phosphates of the gastrocnemius muscle in the knockout mouse with AK deficiency (AK1-/-) and wild type (WT) control muscle over the course of 64 rapid (2/s) isometric tetanic contractions. Near complete depletion of phosphocreatine (PCr) was apparent after 16 contractions in both groups. By approximately 40 contractions, ADP was clearly visible in AK1-/- muscle. This transient concentration of the NMR visible free-ADP was estimated to be ~1.7 mM, and represents the first time free-ADP has been directly measured in contracting skeletal muscle. Such an increase in free-ADP is several fold greater than previously thought to occur. This large accumulation of free-ADP also represents a significant reduction in energy available from ATP, and has implications on cellular processes that depend on a high yield of energy from ATP such as calcium sequestration. Remarkably, the AK1-/- and WT muscles exhibited similar fatigue profiles. Our findings suggest that skeletal muscle is surprisingly tolerant to a large increase in ADP and by extension, a decline in energy from ATP.
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