Deletion of <i>Pofut1</i> in Mouse Skeletal Myofibers Induces Muscle Aging-Related Phenotypes in <i>cis</i> and in <i>trans</i>

Abstract

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 <i>O</i>-fucosyltransferase 1 gene (<i>Pofut1</i>), which encodes a glycosyltransferase required for NotchR-mediated cell-cell signaling, has reduced expression in aging skeletal muscle. Moreover, premature postnatal deletion of <i>Pofut1</i> in skeletal myofibers can induce aging-related phenotypes in <i>cis</i> within skeletal myofibers and in <i>trans</i> 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. <i>Pofut1</i> 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 <i>Pofut1</i> in skeletal muscle, with additional effects on α dystroglycan glycosylation.