Wnt signaling in myogenesis

Abstract

The formation of skeletal muscle is a tightly regulated process that is critically modulated by Wnt signaling. Myogenesis is dependent on the precise and dynamic integration of multiple Wnt signals allowing self-renewal and progression of muscle precursors in the myogenic lineage. Dysregulation of Wnt signaling can lead to severe developmental defects and perturbation of muscle homeostasis. Recent work has revealed novel roles for the non-canonical planar cell polarity (PCP) and AKT/mTOR pathways in mediating the effects of Wnt on skeletal muscle. In this review, we discuss the role of Wnt signaling in myogenesis and in regulating the homeostasis of adult muscle.

Figure 1

Overview of Wnt signaling cascades Wnt signals can be transduced either through the canonical pathway (colored in pink) or different non-canonical pathways. Canonical Wnt signals are mediated by Frizzled (Fzds) receptors and their LRP co-receptors. In the absence of Wnt stimulation, β-catenin forms a degradation complex with APC (adenomatous polyposis coli), Axin and GSK-3 (glycogen synthase kinase-3) (dashed pink line). Phosphorylation of β-catenin by CK1 (casein kinase I) primes β-catenin and GSK-3 for proteasome-mediated degradation. The presence of Wnt ligand results in the activation of Dsh (dishelleved), which leads to a phosphorylation-dependent recruitment of Axin to the LRP co-receptor and disassembly of the β-catenin degradation complex. This leads to an accumulation and stabilization of β-catenin in the cytoplasm and the nuclear translocation of β-catenin. β-catenin complexes with TCF/LEF (T-cell factor/lymphoid enhancer factor) transcription factors and acts as a transcriptional co-activator to induce context-dependent Wnt/β-catenin target genes. Non-canonical Wnt signals are mostly transduced through Fzd receptors without involvement of LRPs. Stimulation of Fzd through Wnt can lead to the activation of PI3K (Phosphatidylinositol 3-kinase), which then activates the AKT/mTOR pathway resulting in increased protein synthesis (shown in green). Other G-protein mediated pathways are the PCP (planar-cell polarity) pathway (shown in blue) leading to the activation of Rac/Rho, JNK (c-Jun N-terminal kinase) and/or ROCK (Rho associated kinase). JNK can induce Jun, which together with Fos, forms the AP-1 early response transcription factor. Both PCP pathways have been implicated in cytoskeletal rearrangements. The Wnt/Ca²⁺ signaling pathway (colored in yellow) is defined by the activation of PLC (phospholipase C) through Wnt/Fzd resulting in an increase in intracellular Ca²⁺ levels, which activate PKCs (protein kinase C) and CamKII (calcium-calmodulin-dependent kinase II) or CN (calcineurin), a phosphatase that activates the transcription factor NFAT (nuclear factor of activated T cell).

Figure 2

Wnt signaling and the embryonic origin of limb and trunk skeletal muscle Developmental myogenesis is influenced by Wnt signaling from tissues surrounding the developing muscle. Wnt1, Wnt3a and Wnt4 are expressed in the dorsal regions of the neural tube. The dorsal ectoderm expresses Wnt4, Wnt6 and Wnt7a. Wnt11 is expressed in the epaxial dermomyotome. These Wnts regulate embryonic muscle development in a spatiotemporal manner.

Figure 3

Effects of exogenous Wnt7a and Wnt3a on regenerating adult skeletal muscle (a) Upon muscle injury satellite cells become activated and fuse with existing fibers or with each other to repair the damaged tissue. This results in newly repaired fibers with centralized nuclei. (b) Wnt7a application to regenerating muscle expands the satellite cell pool through the PCP pathway and induces hypertrophy through the AKT/mTOR signaling cascade. (c) Application of Wnt3a following muscle injury induces the differentiation of satellite cells thereby leading to a depletion of the progenitor cell pool and increased generation of new muscle fibers (hyperplasia). Furthermore, exogenous Wnt3a leads to increased connective tissue deposition and increased myogenic-fibrogenic conversion of satellite cells, and impairs muscle regeneration.