AUTHOR=Zapata Bustos Rocio , Coletta Dawn K. , Galons Jean-Philippe , Davidson Lisa B. , Langlais Paul R. , Funk Janet L. , Willis Wayne T. , Mandarino Lawrence J. 

TITLE=Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle

JOURNAL=Frontiers in Physiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1208186

DOI=10.3389/fphys.2023.1208186

ISSN=1664-042X

ABSTRACT=<p><bold>Introduction:</bold> Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔG<sub>ATP</sub>) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes.</p><p><bold>Methods:</bold><sup>31</sup>P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers.</p><p><bold>Results:</bold> After showing calibrated <sup>31</sup>P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO<sub>2max</sub> (<italic>p</italic> = 0.001) and the 2) slope of the relationship of ΔG<sub>ATP</sub> with the rate of oxidative phosphorylation (<italic>p</italic> = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R<sup>2</sup> = 0.55, <italic>p</italic> = 0.001).</p><p><bold>Conclusion:</bold> Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔG<sub>ATP</sub>, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content <italic>per se</italic> can explain fractional fat oxidation during mild exercise.</p>