Diffusional constraints on energy metabolism in skeletal muscle

Aerobic metabolic flux depends on the diffusion of high-energy phosphate molecules (e.g., ATP and phosphocreatine) from the mitochondria to cellular ATPases, as well as the diffusion of other molecules (e.g., ADP, Pi) back to the mitochondria. Here, we develop an approach for evaluating the influence of intracellular metabolite diffusion on skeletal muscle aerobic metabolism through the application of the effectiveness factor (eta). This parameter provides an intuitive and informative means of quantifying the extent to which diffusion limits metabolic flux. We start with the classical approach assuming an infinite supply of substrate at the fiber boundary, and we expand this model to ultimately include nonlinear boundary and homogeneous reactions. Comparison of the model with experimental data from a wide range of skeletal muscle types reveals that most muscle fibers are not substantially limited by diffusion (eta close to unity), but many are on the brink of rather substantial diffusion limitation. This implies that intracellular metabolite diffusion does not dramatically limit aerobic metabolic flux in most fibers, but it likely plays a role in limiting the evolution of muscle fiber design and function.