The net rate of metabolic processes in cells depends on the competition between the reactivity of the system and the diffusive flow of substrates to the reaction center (Weisz,

The net rate of metabolic processes in cells depends on the competition between the reactivity of the system and the diffusive flow of substrates to the reaction center (Weisz, 1973). For instance, aerobic metabolism depends on the kinetic properties of the mitochondrial enzymes involved in oxidative phosphorylation and on the diffusive flux of substrates such as ADP to the mitochondria. However, most work on aerobic energy metabolism in skeletal muscle has focused only on the catalytic aspects of cellular enzyme systems. This simplification has been based on the reasoning that cellular dimensions tend to be modest (muscle fibers generally range from 10 to 100·μm in diameter; Russell et al., 2000) and intracellular diffusion distances between mitochondria are typically very short in both aerobic and anaerobic skeletal muscle (e.g. Tyler and Sidell, 1984). Thus, diffusion is assumed to be rapid relative to the catalytic capacity of the mitochondria, leading to minimal intracellular gradients in the concentration of metabolites. This approach has been effectively employed to describe some of the major processes of energy metabolism in muscle, and a variety of kinetic models have been developed that closely match experimental data (e.g. Meyer, 1988; Jeneson et al., 1995; Vicini and Kushmerick, 2000; Korzeniewski, 2003). While the value of purely kinetic analyses of muscle energy metabolism is readily apparent, the conditions under which diffusive flux may be important in either limiting the net rate of aerobic processes or influencing the evolution of metabolic pathways are unresolved (Suarez, 2003). The principal hurdle to understanding the role of diffusion and metabolic organization is that most metabolic measurements constitute weighted-averages over an entire cell or tissue, making it difficult to observe localized intracellular events or concentration gradients. However, several studies that employed reaction–diffusion mathematical modeling of The Journal of Experimental Biology 208, 2641-2652 Published by The Company of Biologists 2005 doi:10.1242/jeb.01686