Sarcopenia, the loss of muscle mass and strength during normal aging, involves coordinate changes in skeletal myofibers and the cells that contact them, including satellite cells and motor neurons. Here we show that the protein Ofucosyltransferase 1 gene (Pofut1), which encodes a glycosyltransferase required for NotchR-mediated cell-cell signaling, has reduced expression in aging skeletal muscle. Moreover, premature postnatal deletion of Pofut1 in skeletal myofibers can induce aging-related phenotypes in cis within skeletal myofibers and in trans within satellite cells and within motor neurons via the neuromuscular junction. Changed phenotypes include reduced skeletal muscle size and strength, decreased myofiber size, increased slow fiber (type 1) density, increased muscle degeneration and regeneration in aged muscles, decreased satellite cell self-renewal and regenerative potential, and increased neuromuscular fragmentation and occasional denervation. Pofut1 deletion in skeletal myofibers reduced NotchR signaling in young adult muscles, but this effect was lost with age. Increasing muscle NotchR signaling also reduced muscle size. Gene expression studies point to regulation of cell cycle genes, muscle myosins, NotchR and Wnt pathway genes, and connective tissue growth factor by Pofut1 in skeletal muscle, with additional effects on ␣ dystroglycan glycosylation.KEYWORDS Notch signaling, glycobiology, muscle aging, sarcopenia S arcopenia, the loss of muscle mass and strength during the course of normal aging, has a profound impact on quality of life for the elderly (1-4). About one third of the muscle mass present in young individuals is lost during the aging process. Increased muscle weakness with age can result in decreased ambulation and in more frequent falls and bone fractures. Sarcopenia encompasses a number of phenotypic changes in skeletal muscle, including muscle atrophy, functional reductions in overall muscle strength, muscle wasting, neuromuscular decay and denervation, alterations in muscle fiber populations and patterning, reduced mitochondrial capacity, and the decreased regenerative capacity of satellite cells. Myriad changes in signaling cascades, endocrine hormones, inflammatory factors,  agonists, muscle factors, antioxidants, and energy metabolites have been suggested as contributing factors to sarcopenia, many of them by altering downstream myogenic regulatory factors (1, 2, 4). Similarly, there are a number of factors that control aging in a more global manner (IgfRs, Klotho, p53, Ku-80,