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

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

doi:10.3389/fphys.2023.1208186

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

Front Physiol. 2023 Jul 7:14:1208186. doi: 10.3389/fphys.2023.1208186. eCollection 2023.

Authors

Rocio Zapata Bustos^{1

2}, Dawn K Coletta^{1

2

3}, Jean-Philippe Galons⁴, Lisa B Davidson^{1

2}, Paul R Langlais^{1

2}, Janet L Funk¹, Wayne T Willis^{1

2}, Lawrence J Mandarino^{1

2}

Affiliations

¹ Division of Endocrinology, Department of Medicine, The University of Arizona, Tucson, AZ, United States.
² Center for Disparities in Diabetes, Obesity, and Metabolism, University of Arizona, Tucson, AZ, United States.
³ Department of Physiology, The University of Arizona, Tucson, AZ, United States.
⁴ Department of Medical Imaging, The University of Arizona, Tucson, AZ, United States.

Abstract

Introduction: 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_ATP) 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. Methods: ³¹P-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. Results: After showing calibrated ³¹P-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_2max (p = 0.001) and the 2) slope of the relationship of ΔG_ATP with the rate of oxidative phosphorylation (p = 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 (R² = 0.55, p = 0.001). Conclusion: Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔG_ATP, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content per se can explain fractional fat oxidation during mild exercise.

Keywords: 31 P-magnetic resonance spectroscopy; exercise; fuel selection; insulin sensitivity; mitochondria; skeletal muscle.

Grants and funding

P30 ES006694/ES/NIEHS NIH HHS/United States