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

Area of Science:

• Muscle biology
• Cellular and molecular biology
• Biochemistry

Background:

• Skeletal muscle atrophy involves progressive loss of muscle mass and function.
• The ubiquitin-proteasome system is key for myofibrillar protein breakdown.
• The role of selective autophagy in organelle degradation during atrophy is less understood.

Purpose of the Study:

• To investigate temporal patterns of protein synthesis and degradation in TNF-α-induced muscle atrophy.
• To explore the role of selective autophagy, particularly ER-phagy, in muscle wasting.
• To challenge the view of atrophy as a uniform degradation-centric process.

Main Methods:

• Quantitative, time-resolved in vitro analysis using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC).
• Analysis of C2C12 myotubes undergoing TNF-α-induced atrophy.
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein identification and quantification.

Main Results:

• Muscle atrophy exhibits temporally distinct protein turnover patterns, not uniform degradation.
• Early atrophy shows suppressed synthesis and ribosome turnover; late atrophy involves myofibrillar degradation and metabolic adaptation.
• ER-phagy shifts from homeostasis to a stress-induced program, with receptor accumulation upon autophagy inhibition.

Conclusions:

• ER-phagy is a key contributor to atrophic remodeling in inflammation-induced muscle wasting.
• Receptor-mediated selective autophagy regulates muscle proteostasis during atrophy.
• This study refines understanding of muscle atrophy beyond proteasomal degradation, offering therapeutic avenues for muscle wasting conditions.