The hairpin region of WNT7A is sufficient for binding to the Frizzled7 receptor and to elicit signaling in myogenic cells.

Wnt signaling is essential for embryonic development and tissue homeostasis. So far, little is known about the importance and functional relevance of the different regions in WNT proteins including regions in their C-terminus identified as hairpin and linker. However, it was shown that the C-terminus of WNT7A comprising the linker and the hairpin region is sufficient to elicit signaling. Here, we demonstrate that actually the hairpin region of WNT7A in its C-terminus is fully sufficient to induce non-canonical signaling in myogenic cells while the linker region alone did not show biological activity. Of note, all known non-canonical signaling branches of WNT7A signaling in skeletal muscle were activated by the hairpin region of WNT7A thereby inducing hypertrophy in myotubes, symmetric expansion of satellite stem cells and migration of myoblasts. Furthermore, we demonstrate that the linker region in the C-terminus of WNT7A binds to the FZD7 receptor while it does not activate non-canonical Wnt signaling. However, the hairpin and the linker region of WNT7A can activate canonical Wnt signaling independent of each other suggesting that specificity of downstream signaling might be depending on those specific regions in the C-terminus.

Stimulation of Non-canonical NF-κB Through Lymphotoxin-ß-Receptor Impairs Myogenic Differentiation and Regeneration of Skeletal Muscle.

Myogenic differentiation, muscle stem cell functionality, and regeneration of skeletal muscle are cellular processes under tight control of various signaling pathways. Here, we investigated the role of non-canonical NF-κB signaling in myogenic differentiation, muscle stem cell functionality, and regeneration of skeletal muscle. We stimulated non-canonical NF-κB signaling with an agonistically acting antibody of the lymphotoxin beta receptor (LTßR). Interestingly, we found that stimulation of non-canonical NF-κB signaling through the LTßR agonist impairs myogenic differentiation, muscle stem cell function, and regeneration of skeletal muscle. Furthermore, we show that stimulation of non-canonical NF-κB signaling by the LTßR agonist coincides with activation of canonical NF-κB signaling. We suggest a direct crosstalk between canonical and non-canonical NF-κB signaling during myogenic differentiation which is required for proper myogenic differentiation and thereby regeneration of skeletal muscle.

Wnt7a Counteracts Cancer Cachexia.

Cancer cachexia is a complex metabolic disease so far lacking effective therapy, and it accounts for approximately one third of all cancer-related deaths worldwide. The extracellular ligand Wnt7a has a dual function in skeletal muscle, inducing the anabolic AKT/mammalian target of rapamycin (mTOR) pathway in myofibers and driving muscle stem cell expansion in skeletal muscle, making it a promising candidate for treatment of muscle wasting diseases. In murine and human myotubes, Wnt7a activates the anabolic AKT/mTOR pathway, thereby preventing cachexia-induced atrophy with a single application being sufficient to prevent atrophy independently of the tumor cell type causing cachexia. Addition of Wnt7a also improved activation and differentiation of muscle stem cells in cancer cachexia, a condition under which skeletal muscle regeneration is severely impaired due to stalled muscle stem cell differentiation. Finally, we show that Wnt7a prevents cancer cachexia in an in vivo mouse model based on C26 colon carcinoma cells. Wnt7a has a dual role in cachectic skeletal muscle; that is, it effectively counteracts muscle wasting through activation of the anabolic AKT/mTOR pathway and, furthermore, reverts the loss of muscle stem cell functionality due to cancer cachexia, making Wnt7a a promising candidate for an ameliorative treatment of cancer cachexia.