Autophagy selectively clears ER in TNF-α-induced muscle atrophy

analysis of protein synthesis and degradation in C2C12 myotubes undergoing TNF-α-induced atrophy, using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) coupled with LC-MS/MS. Our data challenges the classical view of atrophy as a uniform, degradation-centric process. Instead, we reveal temporally distinct patterns of selective protein turnover, including differential degradation of myofibrillar, ribosomal, and endoplasmic reticulum (ER)-resident proteins. Early atrophy is characterized by suppressed short-term protein synthesis, increased ubiquitin-ligase expression, proteasomal activation, and ribosome turnover. In contrast, late atrophy features proteasome-dependent myofibrillar protein degradation, selective synthesis, and degradation of mitochondrial and cytoplasmic ribosomes, indicative of metabolic adaptation. Moreover, we identify a temporal shift in autophagic selectivity: from ER homeostasis to a stress-induced ER-degradation program. Notably, autophagy inhibition during atrophy leads to the accumulation of ER-phagy receptors Tex264 and Calcoco1, implicating ER-phagy as a key contributor to atrophic remodeling and highlighting receptor-mediated selective autophagy as a regulatory axis in muscle proteostasis. By elucidating the role of ER-phagy, this study opens avenues for therapeutic interventions targeting proteostasis in inflammation-induced muscle-wasting, contributing to a refined understanding of muscle atrophy beyond proteasomal degradation, particularly in acute inflammatory conditions such as sepsis.