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

doi:10.1016/j.metabol.2022.155242

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

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

15 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 language	English
Article number	155242
Journal	Metabolism: clinical and experimental
Volume	133
DOIs	https://doi.org/10.1016/j.metabol.2022.155242
Publication status	Published - Aug 2022

Keywords

CKD
Mitochondria
n3-PUFA
Skeletal muscle
Uremia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.metabol.2022.155242

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Gortan Cappellari, G., Semolic, A., Ruozi, G., Barbetta, D., Bortolotti, F., Vinci, P., Zanetti, M., Mak, R. H., Garibotto, G., Giacca, M., & Barazzoni, R. (2022). 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. Metabolism: clinical and experimental, 133, Article 155242. https://doi.org/10.1016/j.metabol.2022.155242

@article{2fe81dca583e489c87dab98f9461000f,

title = "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",

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.",

keywords = "CKD, Mitochondria, n3-PUFA, Skeletal muscle, Uremia",

author = "{Gortan Cappellari}, Gianluca and Annamaria Semolic and Giulia Ruozi and Davide Barbetta and Francesca Bortolotti and Pierandrea Vinci and Michela Zanetti and Mak, {Robert H.} and Giacomo Garibotto and Mauro Giacca and Rocco Barazzoni",

note = "Funding Information: This research was partially funded by the European Society for Clinical Nutrition and Metabolism (ESPEN) through a fellowship to AS. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = aug,

doi = "10.1016/j.metabol.2022.155242",

language = "English",

volume = "133",

journal = "Metabolism: clinical and experimental",

issn = "0026-0495",

publisher = "W.B. Saunders Ltd",

}

Gortan Cappellari, G, Semolic, A, Ruozi, G, Barbetta, D, Bortolotti, F, Vinci, P, Zanetti, M, Mak, RH, Garibotto, G, Giacca, M & Barazzoni, R 2022, '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', Metabolism: clinical and experimental, vol. 133, 155242. https://doi.org/10.1016/j.metabol.2022.155242

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. / Gortan Cappellari, Gianluca; Semolic, Annamaria; Ruozi, Giulia et al.
In: Metabolism: clinical and experimental, Vol. 133, 155242, 08.2022.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Gortan Cappellari, Gianluca

AU - Semolic, Annamaria

AU - Ruozi, Giulia

AU - Barbetta, Davide

AU - Bortolotti, Francesca

AU - Vinci, Pierandrea

AU - Zanetti, Michela

AU - Mak, Robert H.

AU - Garibotto, Giacomo

AU - Giacca, Mauro

AU - Barazzoni, Rocco

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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.

KW - CKD

KW - Mitochondria

KW - n3-PUFA

KW - Skeletal muscle

KW - Uremia

UR - http://www.scopus.com/inward/record.url?scp=85132690545&partnerID=8YFLogxK

U2 - 10.1016/j.metabol.2022.155242

DO - 10.1016/j.metabol.2022.155242

M3 - Article

AN - SCOPUS:85132690545

SN - 0026-0495

VL - 133

JO - Metabolism: clinical and experimental

JF - Metabolism: clinical and experimental

M1 - 155242

ER -

Gortan Cappellari G, Semolic A, Ruozi G, Barbetta D, Bortolotti F, Vinci P et al. 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. Metabolism: clinical and experimental. 2022 Aug;133:155242. doi: 10.1016/j.metabol.2022.155242

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

Abstract

Keywords

UN SDGs

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