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Maduramicin ammonium impairs autophagic flux through activating AMPK-mediated eIF2α-ATF4 endoplasmic reticulum stress

Xin Chen1,2,3, Xin Xie1, Chang Liu1

  • 1Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China.

Journal of the Science of Food and Agriculture
|December 11, 2024
PubMed
Abstract

Insights

Maduramicin ammonium impairs skeletal muscle autophagic flux by activating the AMPK-induced eIF2α-ATF4 pathway. This research clarifies the mechanism behind maduramicin ammonium toxicity in muscle tissue.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Maduramicin ammonium (MA) is a coccidiostat linked to skeletal muscle degeneration.
  • Understanding MA's toxicity mechanism in muscle is crucial.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying maduramicin ammonium-induced skeletal muscle toxicity.
  • To elucidate the role of autophagic flux and specific signaling pathways.

Main Methods:

  • Assessed autophagic flux markers (LC3-II, p62) in skeletal myoblast cell lines (C2C12, L6) and animal tissues.
  • Examined eIF2α phosphorylation and ATF4 expression.
  • Investigated the involvement of the AMPK signaling pathway and ISRIB co-treatment.

Main Results:

  • MA exposure increased LC3-II and p62, indicating impaired autophagic flux.
  • MA induced eIF2α phosphorylation and ATF4 expression, which was partially reversed by ISRIB.
  • MA activated AMPK signaling, and its downregulation reversed MA-induced effects on autophagic flux and the eIF2α-ATF4 pathway.

Conclusions:

  • Maduramicin ammonium impairs skeletal muscle autophagic flux.
  • This impairment is mediated by the activation of the AMPK-induced eIF2α-ATF4 pathway.
Keywords:
AMPKATF4autophagyeIF2αmaduramicin ammoniumskeletal muscle

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