Fam83d modulates MAP kinase and AKT signaling and is induced during neurogenic skeletal muscle atrophy
Skeletal muscle atrophy is a serious health condition that can arise due to aging, cancer, corticosteroid exposure, and denervation. Previous work comparing gene expression profiles in control and denervated muscle tissue revealed for the first time that Fam83d is expressed in skeletal muscle and is significantly induced in response to denervation. Quantitative PCR and Western blot analysis found that Fam83d is more highly expressed in proliferating myoblasts compared to differentiated myotubes. Characterization of the transcriptional regulation of Fam83d showed that ectopic expression of myogenic regulatory factors inhibits Fam83d reporter gene activity. To assess where Fam83d is localized in the cell, Fam83d was fused with green fluorescent protein, expressed in C2C12 cells, and found to localize in a punctate manner to the cytoplasm of muscle cells. To assess function, Fam83d was ectopically expressed in cultured muscle cells and markers of muscle cell differentiation, the MAP Kinase signaling pathway, and the AKT signaling pathway were analyzed. Fam83d overexpression resulted in significant repression of myosin heavy chain and myogenin expression, while phosphorylated ERK and AKT were also significantly repressed. Interestingly, inhibition of the 26S proteasome and the MAP kinase signaling pathway both resulted in stabilization of Fam83d during muscle cell differentiation. Finally, Fam83d has a putative phospholipase D-like domain that appears to be necessary for destabilizing casein kinase Iα and inhibiting ERK phosphorylation in cultured myoblasts. The discovery that Fam83d is expressed in skeletal muscle combined with the observation that Fam83d, a potential modulator of MAP kinase and AKT signaling, is induced in response to neurogenic atrophy helps further our understanding of the molecular and cellular events of skeletal muscle wasting.
Digital Object Identifier (DOI)
Cooper, L. M., Hanson, A., Kavanagh, J. A., & Waddell, D. S. (2020). Fam83d modulates MAP kinase and AKT signaling and is induced during neurogenic skeletal muscle atrophy. Cellular signalling, 70, 109576. https://doi.org/10.1016/j.cellsig.2020.109576