ADP is the dominant controller of AMP-activated protein kinase activity dynamics in skeletal muscle during exercise

• Published in: PLoS computational biology Vol. 16; no. 7; p. e1008079
• Main Authors: Coccimiglio, Ian F, Clarke, David C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-07-2020; Public Library of Science (PLoS)
• Subjects: Adaptation; Adaptations; Adenine; Adenosine diphosphate; Adenosine Diphosphate - chemistry; Adenosine Diphosphate - metabolism; Adenosine Diphosphate - pharmacokinetics; Allosteric properties; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - metabolism; Analysis; Animals; Binding; Binding sites; Biology; Biology and Life Sciences; Chemical properties; Computational Biology; Controllers; Cyclic AMP-dependent protein kinases; Dynamics; Energy demand; Enzyme kinetics; Exercise; Exercise - physiology; Exercise intensity; Fitness training programs; Humans; Hypotheses; Investigations; Kinases; Kinesiology; Mathematical models; Medicine and Health Sciences; Metabolism; Mice; Models, Biological; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Muscles; Musculoskeletal system; Nucleotides; Ordinary differential equations; Parameter sensitivity; Pharmacology; Phosphatase; Phosphates; Phosphorylation; Physical fitness; Physical training; Physiological aspects; Physiology; Proteins; Sensitivity analysis; Signal Transduction - physiology; Skeletal muscle; Transcription factors; Canada
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1008079

Exercise training elicits profound metabolic adaptations in skeletal muscle cells. A key molecule in coordinating these adaptations is AMP-activated protein kinase (AMPK), whose activity increases in response to cellular energy demand. AMPK activity dynamics are primarily controlled by the adenine nucleotides ADP and AMP, but how each contributes to its control in skeletal muscle during exercise is unclear. We developed and validated a mathematical model of AMPK signaling dynamics, and then applied global parameter sensitivity analyses with data-informed constraints to predict that AMPK activity dynamics are determined principally by ADP and not AMP. We then used the model to predict the effects of two additional direct-binding activators of AMPK, ZMP and Compound 991, further validating the model and demonstrating its applicability to understanding AMPK pharmacology. The relative effects of direct-binding activators can be understood in terms of four properties, namely their concentrations, binding affinities for AMPK, abilities to enhance AMPK phosphorylation, and the magnitudes of their allosteric activation of AMPK. Despite AMP's favorable values in three of these four properties, ADP is the dominant controller of AMPK activity dynamics in skeletal muscle during exercise by virtue of its higher concentration compared to that of AMP.