Acta Neuropathol (1992) 84:135 - 140 kta N i6pa|hologJca 9 Springer-Verlag1992 Modifications in myotendinous junction structure following denervation* J. G. Tidball and D. M. Quan Department of PhysiologicalScience and Jerry Lewis Neuromuscular Research Center, Universityof California, Los Angeles, CA 90024-1527, USA Received October 8, 1991/Revised, acceptedFebruary 10, 1992 Summary. Changes in the structure of myotendinous junctions in response to peripheral nerve lesions are examined by transmission electron microscopy and morphometric analysis. Modifications in the folding of the plasma membrane at myotendinous junctions rela- tive to the cross-sectional area of myofibrils terminating at the membrane are evaluated quantitatively using a morphometric analysis in which the muscle cell pro- cesses at the myotendinous junction are modeled as circular paraboloids. Denervated frog semitendinosus muscles were analyzed at 2, 4 and 8 weeks following denervation and compared to innervated, contralateral controls. No significant differences were found in rela- tive folding of junctional plasma membranes between any two data sets, although myofibril diameter decreased over time following denervation. This shows that junctional plasma membrane and associated junc- tional structures, such as basement membrane, are removed from the myotendinous junction at a rate similar to that of myofibril thinning, thereby keeping constant the ratio between junction area and myofibril cross-sectional area. Electron microscopic observations indicate that 4 weeks post-denervation is the most active stage of junction remodeling of the time points sam- pled. Key words: Muscle - Nerve injury - Myotendinous junction - Myofibril - Muscle atrophy Denervation of skeletal muscle leads to stereotypic sequence of structural and molecular changes in muscle that accompany muscle atrophy. For example, type I muscle fibers undergo a shift in physiological character- istics to resemble type II fibers following denervation * Supported by a grant from the National Institutes of Health (AR-40343) Correspondence to: J. G. Tidball (address see above) (e.g., [2, 8, 12, 22]) in a slow-to-fast fiber conversion that is characteristic of not only denervation atrophy, but also disuse atrophy and other neurogenic atrophies. This conversion is typified by a change in myosin isoform expression. Electron microscopic observations show that the sequence of structural changes occurring in muscle following denervation are similar in a variety of verte- brates, including frogs [3, 13] guinea pigs [22] and rats [14, 15]. The structural modifications seen in these animals following denervation are similar to those seen in human skeletal muscle accompanying a variety of neurogenic atrophies including Werdnig-Hoffman's dis- ease, Kugelberg-Welander's disease, spinal muscular atrophy, peripheral neuritis [16] and amyotrophic lateral sclerosis [1]. Common characteristics for each of these diseases and injuries is a reduction in cell cross-sectional area and a loss of myofibrillar material, especially myofilaments that lie peripherally in each myofibril [1, 11, 13, 15, 16, 22].This indicates that force production by any single muscle cell will decline, as myofibrils are lost. Although the response of myofibrils to denervation is catabolic, the response of muscle connective tissue is not. Denervation of guinea pig hindlimb muscles leads to an increase in the absolute quantity of collagen in muscle [22], indicating that denervation has in anabolic effect on muscle fibroblasts through some unknown mechanism. Denervation of muscle has no, or a lesser, effect on the basement membrane of muscle than on the enclosed myofibrillar components. As muscle fiber size decreases during denervation, the size of the enclosing basement membrane appears to be little changed, so that the distance between basement membrane and cell membrane increases and the basement membrane lies in folds at the cell surface [3, 15]. These modifications of myofibrillar and connective tissue components of muscle in response to denervation suggest the possibility that the junctions that couple these musculoskeletal components may also undergo structural modifications following denervation. Obser-