Depletion of the mRNA translation initiation inhibitor, programmed cell death protein 4 (PDCD4), impairs L6 myotube formation

The mechanistic (mammalian) target of rapamycin complex 1 (mTORC1) signaling is vital for optimal muscle mass and function. Although the significance of mTORC1 in stimulating muscle growth is unequivocal, evidence in support of its role during muscle regeneration is less clear. Here, we showed that the abundance (protein and mRNA) of the mTORC1/S6K1 substrate, programmed cell death protein 4 (PDCD4), is upregulated at the onset of differentiation of L6 and C2C12 cells. The increase in PDCD4 was not associated with any changes in S6K1 activation, but the abundance of beta transducing repeat‐containing protein (β‐TrCP), the ubiquitin ligase that targets PDCD4 for degradation, increased. Myoblasts lacking PDCD4 showed impaired myotube formation and had markedly low levels of MHC‐1. Analysis of poly (ADP‐ribose) Polymerase (PARP), caspase 7 and caspase 3 indicated reduced apoptosis in PDCD4‐deficient cells. Our data demonstrate a role for PDCD4 in muscle cell formation and suggest that interventions that target this protein may hold promise for managing conditions associated with impaired myotube formation. We showed that the abundance of PDCD4, an mTORC1/S6K1 substrate, is upregulated during myotube formation. Cells lacking this protein did not form myotubes; they also have impaired regulation of apoptosis. These data demonstrate PDCD4 as a critical regulator of muscle cell differentiation.