lambeth

Title

A Computational Model for Glycogenolysis in Skeletal Muscle

Authors

MELISSA J. LAMBETH1 and MARTIN J. KUSHMERICK

Affiliations

Department of Bioengineering, Department of Radiology, and Department of Physiology and Biophysics,University of Washington, Seattle, WA

Abstract

A dynamic model of the glycogenolytic pathway to lactate in skeletal muscle was constructed with mammalian kinetic parameters obtained from the literature. Energetic buffers relevant to muscle were included. The model design features stoichiometric constraints, mass balance, and fully reversible thermodynamics as defined by the Haldane relation. We employed a novel method of validating the thermodynamics of the model by allowing the closed system to come to equilibrium; the combined mass action ratio of the pathway equaled the product of the individual enzymes' equilibrium constants. Adding features physiologically relevant to muscle - a fixed glycogen concentration, efflux of lactate, and coupling to an ATPase - allowed for a steady-state flux far from equilibrium. The main result of our analysis is that coupling of the glycogenolytic network to the ATPase transformed the entire complex into an ATPase driven system. This steady-state system was most sensitive to the external ATPase activity and not to internal pathway mechanisms. The control distribution among the internal pathway enzymes - although small compared to control by ATPase - depended on the flux level and fraction of glycogen phosphorylase a. This model of muscle glycogenolysis thus has unique features compared to models developed for other cell types.

Journal

Annals of Biomedical Engineering, Vol. 30, pp. 808-827, 2002

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Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Global parameters

Local parameters

Assignment rules

Rate rules

Algebraic rules