Faculty Collaboration Database

Modeling cellular metabolism and energetics in skeletal muscle: large-scale parameter estimation and sensitivity analysis. IEEE Trans Biomed Eng 2008 Apr;55(4):1298-318

Date

04/09/2008

Pubmed ID

18390321

DOI

10.1109/TBME.2007.913422

Scopus ID

2-s2.0-41149083382 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

Skeletal muscle plays a major role in the regulation of whole-body energy metabolism during physiological stresses such as ischemia, hypoxia, and exercise. Current experimental techniques provide relatively little in vivo data on dynamic responses of metabolite concentrations and metabolic fluxes in skeletal muscle to such physiological stimuli. As a complementary approach to experimental measurements and as a framework for quantitatively analyzing available in vivo data, a physiologically based model of skeletal muscle cellular metabolism and energetics is developed. This model, which incorporates key transport and reaction processes, is based on dynamic mass balances of 30 chemical species in capillary (blood) and tissue (cell) domains. The reaction fluxes in the cellular domain are expressed in terms of a generalized Michaelis?Menten equation involving energy controller ratios ATP/ADP and ATP/ADP and NADH/NAD+ . This formalism introduces a large number of unknown parameters ( approximately 90). Estimating these parameters from in vivo sparse data and evaluating dynamic sensitivities of the model outputs with respect to these parameters is a challenging problem. Parameter estimation is accomplished using an efficient, nonlinear, constraint-based, optimization algorithm that minimizes differences between available experimental data and corresponding model outputs by explicitly utilizing equality constraints on resting fluxes and concentrations. With the estimated parameter values, the model is able to simulate dynamic responses to reduced blood flow (ischemia) of key metabolite concentrations and metabolic fluxes, both measured and nonmeasured. A general parameter sensitivity analysis is carried out to determine and characterize the parameters having the most and least effects on the measured outputs.

Author List

Dash RK, Li Y, Kim J, Saidel GM, Cabrera ME

Author

Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Computer Simulation
Energy Metabolism
Humans
Models, Biological
Muscle Fibers, Skeletal
Muscle, Skeletal
Reproducibility of Results
Sensitivity and Specificity