Metabolic and functional consequences of adenylate kinase deficiency in skeletal muscle

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The primary function of skeletal muscle is to generate tension, and this ultimately occurs through ATP utilization. An increase in ADP and a depression in the cellular energy state are thought to be limited by the adenylate kinase (AK) reaction during high energy demands. AMP production through AK is also thought to be important for metabolic signaling, particularly during moderate energy demands. Thus, AK deficiency in muscle was evaluated during highly demanding and moderately demanding muscle contractions, using the AK1 knockout mouse (AK1-/-). The results demonstrate that AK deficiency leads to a marked elevation in free-ADP (1.5mM) at high energy demands, many fold greater than previously thought possible. These results call into question previously held views concerning the energy required for normal muscle function, because the performance was remarkably tolerant of ADP accumulation. At lower energy demands, AMPK phosphorylation was tempered in AK1-/- muscle consistent with reduced AMP production. Interestingly, other indicators of AMPK activity suggest that AMPK activation occurs normally, despite reduced AMPK phosphorylation. Thus, AK is critically important for the management of ADP during high energy demands, and may result in altered metabolic signaling at low energy demands.