Etiology and pathogenesis of sarcopenia, the progressive decline in skeletal muscle mass and strength that occurs with aging, are still poorly understood. We recently found that overexpression of the neural serine protease neurotrypsin in motoneurons resulted in the degeneration of their neuromuscular junctions (NMJ) within days. Therefore, we wondered whether neurotrypsin‐dependent NMJ degeneration also affected the structure and function of the skeletal muscles. Using histological and functional analyses of neurotrypsin‐overexpressing and neurotrypsin‐deficient mice, we found that overexpression of neurotrypsin in motoneurons installed the full sarcopenia phenotype in young adult mice. Characteristic muscular alterations included a reduced number of muscle fibers, increased heterogeneity of fiber thickness, more centralized nuclei, fiber‐type grouping, and an increased proportion of type I fibers. As in age‐dependent sarcopenia, excessive fragmentation of the NMJ accompanied the muscular alterations. These results suggested the destabilization of the NMJ through proteolytic cleavage of agrin at the onset of a pathogenic pathway ending in sarcopenia. Studies of neurotrypsin‐deficient and agrin‐overexpressing mice revealed that old‐age sarcopenia also develops without neurotrypsin and is not prevented by elevated levels of agrin. Our results define neurotrypsin‐ and age‐dependent sarcopenia as the common final outcome of 2 etiologically distinct entities.—Bütikofer, L., Zurlinden, A., Bolliger, M. F., Kunz, B., Sonderegger, P. Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia. FASEB J. 25, 4378–4393 (2011). www.fasebj.org