Review Volume 3, Issue 8 pp 702—715

Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia


Figure 3. The mechanism of iNOS-induced muscle wasting. TNFα, a key proinflammatory cytokine in the induction of muscle wasting, binds to its receptor, activating a signaling pathway that culminates in the activation of NF-κB. NF-κB then enhances the transcription of the iNOS transcript, which is subsequently bound by HuR at an ARE in the 3'-UTR and stabilized. This results in a dramatic increase in iNOS mRNA levels, resulting in enhanced translation of the iNOS protein. iNOS converts L-arginine into citrulline, releasing NO in the process. Several NO-dependent pathways may be responsible for the induction of muscle wasting. First, NO diffuses out of the cell where it combines with superoxide (O2-) to form peroxynitrite (ONOO-). Peroxynitrite then diffuses back into the cell, selectively inhibiting MyoD, an important myogenic transcription factor, at the post-transcriptional level. Loss of MyoD leads to a reduction in MyHC expression, compromising the integrity of the myofibrillar protein complex. Second, NO-production leads to the oxidative modification of Jun-D, which, together with myogenin, regulates several key skeletal muscle-specific proteins, like CKM. Finally, NO-production may inhibit protein synthesis by inhibiting mTOR signaling and by increasing eIF2α and eEF2 phosphorylation, though the mechanism by which this occurs is uncertain. It is also unclear whether NO causes these last two effects directly, or through the formation of peroxynitrite.