PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy.

Summary

In a CLP sepsis model, PACS2 levels fell, MAM integrity deteriorated, and FAM134B-dependent ER-phagy and muscle wasting ensued. AAV-mediated PACS2 overexpression restored MAM integrity, activated ERK (but not p38/JNK), inhibited TFEB nuclear translocation, suppressed ER-phagy, and rescued muscle structure and function; ERK inhibition abrogated these effects.

Key Findings

• Sepsis (CLP) caused 56% reduction of PACS2 at 96 h with 25% MAM integrity loss and activation of FAM134B-mediated ER-phagy (all p<0.05).
• AAV-PACS2 overexpression restored MAM integrity by 28% and reduced FAM134B by 43%, attenuating ER-phagy and muscle atrophy (p<0.01).
• PACS2 increased p-ERK by 55% (p<0.01) without affecting p-p38 or p-JNK; ERK inhibition (SCH772984) abolished benefits.
• Protection correlated with inhibition of TFEB nuclear translocation and downstream ER-phagy gene expression.

Clinical Implications

While preclinical, findings nominate PACS2/MAM stabilization and ERK–MAPK–TFEB modulation as candidate strategies to prevent or treat sepsis-induced myopathy and ICU-acquired weakness.

Limitations

• Preclinical mouse study; no human interventional validation
• Sample sizes per experiment not specified in abstract; sex- and strain-specific effects possible

Future Directions

Validate PACS2/MAM-targeted strategies in large-animal sepsis models, quantify dose–response for ERK–TFEB modulation, and develop biomarkers of MAM integrity for early identification and stratification of ICU patients.