Simulating Metabolic Flexibility in Low Energy Expenditure Conditions Using Genome-Scale Metabolic Models

Abstract

Metabolic flexibility is the ability of an organism to adapt its energy source based on nutrient availability and energy requirements. In humans, this ability has been linked to cardio-metabolic health and healthy aging. Genome-scale metabolic models have been employed to simulate metabolic flexibility by computing the Respiratory Quotient (RQ), which is defined as the ratio of carbon dioxide produced to oxygen consumed, and varies between values of 0.7 for pure fat metabolism and 1.0 for pure carbohydrate metabolism. While the nutritional determinants of metabolic flexibility are known, the role of low energy expenditure and sedentary behavior in the development of metabolic inflexibility is less studied. In this study, we present a new description of metabolic flexibility in genome-scale metabolic models which accounts for energy expenditure, and we study the interactions between physical activity and nutrition in a set of patient-derived models of skeletal muscle metabolism in older adults. The simulations show that fuel choice is sensitive to ATP consumption rate in all models tested. The ability to adapt fuel utilization to energy demands is an intrinsic property of the metabolic network.

Keywords: energy expenditure; metabolic flexibility; respiratory quotient.

Figure 1

Simplified representation of two different descriptions of the fast to fed transition in a constraint-based metabolic model. (A) Architecture of the simulation presented in [11]: change in nutrient availability during the fast to fed transition is modeled by modulating the flux through glucose and palmitate transporters, the reactions transporting substrates between the external and the cytoplasm compartments (black arrows). Production of ATP, creatinine phosphate (CrP), glycogen and triglycerides (TG) was used as objective reaction (red arrow). The availability of glucose and palmitate in the external compartment is assumed to be infinite. (B) Architecture of the simulation presented in this study. The fast to fed transition is modeled by modulating the amount of nutrients available in the external compartment through exchange reactions (black arrows). ATP phosphodiester bond hydrolysis (ATPH) is used as objective function (red arrow). The models are free to choose the optimal mix of substrates to optimize the flux through the objective function. RQ is defined as the ratio between CO$${}_2$$ efflux and O$${}_2$$ influx (blue arrows) in both implementations. Blank arrows represent reactions that were left unbounded.

Figure 2

Simulations of fast to fed transition highlight heterogeneity of model predictions. Validation of our of the fast-to fed transition. (A) RQ values predicted by three human constraint-based models (Recon2.2, Recon3D and MitoCore) during the fast to fed transition with the objective function ATPH left unconstrained (upper bound ATPH = 1000 mM/gDw/h). X axis: upper bound values for palmitate and glucose exchange reactions during the fast to fed transition (in mM/gDw/h). (B) ATP yields for glucose and palmitate across the three models.

Figure 3

RQ is sensitive to changes in ATP hydrolysis rate. RQ values during the fast to fed transition simulated for different rates of ATP hydrolysis in Recon2.2 (A), Recon3D (B) and MitoCore (C). The upper bound of the objective reaction (ATPH) was progressively decreased from 200 mM/gDw/h (blue line) to 35 mM/gDw/h (red line). In all models, as ATP hydrolysis rate decreases, RQ values approaches a constant value (RQ = 1.0) faster during the fast to fed transition.

Figure 4

RQ changes are independent on intake fluxes. Predicted RQ for varying levels of ATPH upper bound. Intake bounds for palmitate and glucose were kept constant. Glucose uptake upper bound: 4.5 mmol/gDw/h. Palmitate uptake upper bound: 0.38 mmol/gDw/h.

Figure 5

Simulations in low energy expenditure conditions show heterogeneity of individualized models’ predictions. RQ values predicted by a set of 24 patient-derived models of skeletal muscle metabolism. (A) High energy expenditure conditions (ATPH bound = 1000 mM/gDw/h). All models predict the same RQ values during the fast to fed transition and have overlapping RQ profiles. (B) Comparison of trained vs. untrained subgroups. Low energy expenditure condition (ATPH upper bound = 35 mM/gDw/h). In this condition, untrained models predicted lower RQ values on average and low variability between the fast and fed conditions than trained models. These two phenotypes are associated with metabolic inflexibility.

Figure 6

Increased utilization of oxidative phosphorylation (OXPHOS) in trained models in response to low energy demands. Percentage of total cellular ATP produced was measured as flux through the adenine nucleotide translocator (ANT) reaction (reaction ID: ATPtm). Twenty-one models were included in the analysis (N trained = 12, N untrained = 9). (A) High energy expenditure. (B) Low energy expenditure. In low EE conditions, trained models produce a higher percentage of total ATP from OXPHOS than untrained ones. Untrained models show a larger variance in the percentage of total ATP obtained from OXPHOS than untrained models.