Developmental pathways may be play a role in adult cell survival. However, whether they interact with longevity/cell survival pathways to confer protection against disease-associated proteotoxicity remains largely unknown. We previously reported that the inhibition of key longevity modulators such as the deacetylase sir-2.1/SIRT1 (Sir2) and its target daf-16/FoxO protects transgenics nematodes from muscle cell decline and abnormal motility produced by the expression of mutant (polyalanine-expanded) PABPN1, the oculopharyngeal muscular dystrophy (OPMD) protein. Here, we report that canonical Wnt signaling (i) modulates muscular pathology in mutant PABPN1 nematodes, and (ii) cooperates with the Sir2-FoxO longevity pathway to confer protection against mutant PABPN1 toxicity at the cellular and behavioral levels. Mutant PABPN1 toxicity was modified by genes along the canonical Wnt pathway, several of which depend on daf-16 for activity. ss-catenin and pop-1/TCF RNAi suppressed the protection from mutant PABPN1 confered by loss-of-function mutations in sir-2.1 and daf-16. Moreover, the aggravation of muscle cell pathology by increased sir-2.1 dosage was reversed by ss-catenin and pop-1 RNAi. The chemical inhibition of GSK-3ss, a repressor of ss-catenin activity, protected against mutant PABPN1 toxicity in a daf-16-dependent manner, which is consistent with a cross-talk between ss-catenin signaling and Sir2-FoxO signaling in protecting from mutant PABPN1 toxicity. Our data reveal that canonical Wnt signaling and Sir2-FoxO signaling interact to modulate diseased muscle survival, and indicate that GSK-3ss inhibitors and sirtuin inhibitors both have therapeutic potential for muscle protection in OPMD.