Some major pathways controlling protein breakdown in skeletal muscle. Some major pathways controlling protein breakdown in skeletal muscle. Ubiquitination encompasses the targeting of structural and regulatory muscle proteins for degradation by proteasomes. This process is inhibited by activation of the IGF–Akt pathway. Specifically, binding of IGF to the IGF-IR at the muscle sarcolemma induces phosphorylation of Akt, leading to the phosphorylation of FOXO transcription factors, causing their nuclear exit and downregulation of MAFbx and MuRF1, two E3 ubiquitinligases necessary for ubiquitination. The NF–κB pathway is an alternative route to transcriptional regulation of MuRF1, as well as the E2-conjugating enzyme UBE2H. This pathway stimulates muscle atrophy in response to the pro-inflammatory cytokine TNF-α. NF–κB is normally bound to Iκ-B proteins in the cytoplasm. Upon the phosphorylation of this complex via a signal transduction cascade induced by TNF-α binding to its receptor, NF–κB and Iκ-B dissociate, allowing NF–κB to enter the nucleus and transcriptionally activate its target genes to induce atrophy. The calpain family constitutes a major cytosolic protein breakdown pathway, and three widely expressed members are expressed in teleost muscle, including CAPN11. These calpains regulate many other physiological processes in muscle, including myoblast fusion. Lysosomes are cellular organelles containing acid hydrolase enzymes. Ian A. Johnston et al. J Exp Biol 2011;214:1617-1628 © 2011.