The in-vivo uptake of exogenously applied horseradishperoxidase and the activities of the lysosomal enzymesacid phosphatase and cathepsin D were studied histochemicallyand/or biochemically in innervated and2-14 day-denervated tibialis anterior muscles of the mouse.The biochemically determined uptake of horseradish peroxidaseshowed a large increase already 4 days after denervation.The activities of the lysosomal enzymes increased ina more gradual fashion, and only cathepsin D showed anincrease in activity when expressed as total activity per muscle.Histochemically horseradish peroxidase was found tobe localized in muscle fibres in characteristic spindle-shapedsegments after denervation. The main increase in thenumber of such segments per transverse section of the muscleoccurred between 3 and 6 days after denervation. Inserial sections these segments frequently showed positivestaining also for acid phosphatase.It is concluded that exogenously applied horseradishperoxidase is taken up into the lysosomal system, whichafter denervation becomes organized into characteristicspindle-shaped segments in the muscle fibres. The endocyticactivity of muscle fibres increases early after denervation.This is followed by a more gradual increase in activity oflysosomal enzymes and finally by an organization of thelysosomal system into characteristic spindle-shaped segments.The results are compatible with the working hypothesisthat increased endocytosis may initiate lysosomal activationin denervated skeletal muscle.