Wnt/ -catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy

Armstrong, Dustin D., and Karyn A. Esser. Wnt/ -catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy. Am J Physiol Cell Physiol 289: C853–C859, 2005. First published May 11, 2005; doi:10.1152/ajpcell.00093.2005.— -Catenin is a transcriptional activator shown to regulate the embryonic, postnatal, and oncogenic growth of many tissues. In most research to date, -catenin activation has been the unique downstream function of the Wnt signaling pathway. However, in the heart, a Wnt-independent mechanism involving Akt-mediated phosphorylation of glycogen synthase kinase (GSK)-3 was recently shown to activate -catenin and regulate cardiomyocyte growth. In this study, results have identified the activation of the Wnt/ -catenin pathway during hypertrophy of mechanically overloaded skeletal muscle. Significant increases in -catenin were determined during skeletal muscle hypertrophy. In addition, the Wnt receptor, mFrizzled (mFzd)-1, the signaling mediator disheveled-1, and the transcriptional co-activator, lymphocyte enhancement factor (Lef)-1, are all increased during hypertrophy of the overloaded mouse plantaris muscle. Experiments also determined an increased association between GSK-3 and the inhibitory frequently rearranged in advanced T cell-1 protein with no increase in GSK-3 phosphorylation (Ser9). Finally, skeletal muscle overload resulted in increased nuclear -catenin/Lef-1 expression and induction of the transcriptional targets c-Myc, cyclin D1, and paired-like homeodomain transcription factor 2. Thus this study provides the first evidence that the Wnt signaling pathway induces -catenin/Lef-1 activation of growth-control genes during overload induced skeletal muscle hypertrophy.