n-3 PUFA dietary lipid replacement normalizes muscle mitochondrial function and oxidative stress through enhanced tissue mitophagy and protects from muscle wasting in experimental kidney disease

Gianluca Gortan Cappellari, Annamaria Semolic, Giulia Ruozi, Davide Barbetta, Francesca Bortolotti, Pierandrea Vinci, Michela Zanetti, Robert H. Mak, Giacomo Garibotto, Mauro Giacca, Rocco Barazzoni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Introduction and methods: Skeletal muscle mitochondrial dysfunction may cause tissue oxidative stress and consequent catabolism in chronic kidney disease (CKD), contributing to patient mortality. We investigated in 5/6-nephrectomized (Nx) rats the impact of n3-polyunsaturated fatty-acids (n3-PUFA) isocaloric partial dietary replacement on gastrocnemius muscle (Gm) mitochondrial master-regulators, ATP production, ROS generation and related muscle-catabolic derangements. Results: Nx had low Gm mitochondrial nuclear respiratory factor-2 and peroxisome proliferator-activated receptor gamma coactivator-1alpha, low ATP production and higher mitochondrial fission-fusion protein ratio with ROS overproduction. n3-PUFA normalized all mitochondrial derangements and pro-oxidative tissue redox state (oxydized to total glutathione ratio). n3-PUFA also normalized Nx-induced muscle-catabolic proinflammatory cytokines, insulin resistance and low muscle weight. Human uremic serum reproduced mitochondrial derangements in C2C12 myotubes, while n3-PUFA coincubation prevented all effects. n3-PUFA also enhanced muscle mitophagy in-vivo and siRNA-mediated autophagy inhibition selectively blocked n3-PUFA-induced normalization of C2C12 mitochondrial ROS production. Conclusions: In conclusion, dietary n3-PUFA normalize mitochondrial master-regulators, ATP production and dynamics in experimental CKD. These effects occur directly in muscle cells and they normalize ROS production through enhanced mitophagy. Dietary n3-PUFA mitochondrial effects result in normalized catabolic derangements and protection from muscle wasting, with potential positive impact on patient survival.

Original languageEnglish
Article number155242
JournalMetabolism: clinical and experimental
Volume133
DOIs
Publication statusPublished - Aug 2022

Keywords

  • CKD
  • Mitochondria
  • n3-PUFA
  • Skeletal muscle
  • Uremia

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