Cross-innervations and re-innervations were performed on the slow ("red") m. soleus and the fast ("white") m. extensor digitorurn of the rabbit. Innervation of the slow soleus muscle with "fast" motor neurons causes a significant change of the metabolic type of the muscle. This transformation consists in a parallel increase of the activity levels of glycogen phosphorylase, of all the investigated glycolytic enzymes (phosphofructokinase, triosephosphate isomerase, triosephosphate dehydrogenase, phosphoglycerate kinase, glycerate phosphomutase, phosphopyruvate hydratase, lactate dehydrogenase), of adenylate kinase and mitochondrial glycerolphosphate dehydrogenase. A concomitant and parallel decrease is found in the activity levels of extramitochondrial hexokinase, and alanine aminotransferase, of all the investigated enzymes of the citric acid cycle (intramitochondrial citrate synthase, and succinate dehydrogenase, extra-and intramitochondrial malate dehydrogenase, and NADP isocitrate dehydrogenase), of intramitochondrial 3-hydroxyacyl-CoA dehydrogenase and glutamate dehydrogenase, and of extra-and intramitrochondrial aspartate aminotransferase. I n spite of the marked changes in absolute activities, no alterations occur with regard to the ratios of enzymes and enzyme groups which by comparison of functionally different muscles have been classified as constant. Changes in the activity ratios concern the same enzymes which in previous studies have been shown to be characteristic of the metabolic type (phosphorylase/hexokinase, triosephosphate dehydrogenaselcitrate synthase, lactate dehydrogenaselcitrate synthase, triosephosphate dehydrogenase/3-hydroxyacyl-CoA dehydrogenase, adenylate kinaselcreatine kinase). The alterations show that a conversion of the metabolic type from "slow" to "fast" takes place and indicate a specific influence of the innervation on metabolic differentiation in muscle, that is the control of a specific pattern of enzyme synthesis. Due to the obvious failure of innervation of the fast extensor muscle with "slow" motor neurons from the tibia1 nerve, no significant changes were observed in this muscle.As has been outlined in earlier communications [l-51, metabolic differentiation of muscle tissue is reflected a t the level of enzymatic organization, and may be visualized best by comparative analysis of activity levels and activity ratios of key enzymes in energy-supplying metabolism. A classification of different "metabolic types" of vertebrate muscles