Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle.

Daniele Lettieri-Barbato,Maria Rosa Ciriolo,Katia Aquilano,Stefano Maria Cannata,Viviana Casagrande,Marcia B Aguila

doi:10.1371/journal.pone.0195912

Daniele Lettieri-Barbato, Maria Rosa Ciriolo + Show 4 more

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https://doi.org/10.1371/journal.pone.0195912

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Abstract

A large body of evidence suggests that persistent dietary fat overload causes mitochondrial dysfunction and systemic metabolic gridlock. Mitochondrial and lipid metabolism in skeletal muscle (SkM) are severely affected upon persistent high fat diet (HFD) leading to premature tissue aging. Here, we designed weekly cycles of fasting (called as time-controlled fasting, TCF) and showed that they were effective in limiting mitochondrial damage and metabolic disturbances induced by HFD. Specifically, TCF was able to prevent the decline of adipose triglyceride lipase (Atgl), maintain efficient mitochondrial respiration in SkM as well as improve blood glucose and lipid profile. Atgl was found to be the mediator of such preventive effects as its downregulation or up-regulation in C2C12 myotubes triggers mitochondrial alteration or protects against the deleterious effects of high fat levels respectively. In conclusion, TCF could represent an effective strategy to limit mitochondrial impairment and metabolic inflexibility that are typically induced by modern western diets or during aging.

Highlights

Mitochondrial respiratory function progressively declines with age especially in highly oxidative tissues such as skeletal muscle (SkM) resulting in a raise of reactive oxygen species (ROS) emission and oxidative damage [1]
We found that in mice fed with high fat diet (HFD), time-controlled fasting (TCF) was able to prevent alteration of systemic metabolism and maintain high Adipose triglyceride lipase (Atgl) levels and mitochondrial efficiency concomitant to decreased oxidative damage in SkM
Through gene expression data analyses of publically available data (GEO accession number GDS3078), we found that the glucose transporter Glut-4 resulted down-regulated as soon as 28 days in SkM of mice fed with HFD (45% calories from fats) (Fig 1C, grey bars)

Summary

Introduction

Mitochondrial respiratory function progressively declines with age especially in highly oxidative tissues such as skeletal muscle (SkM) resulting in a raise of reactive oxygen species (ROS) emission and oxidative damage [1]. In addition to this intrinsic mitochondrial dysfunction, lifestyle factors may affect mitochondrial activity [2]. Obesity and type 2 diabetes (T2D) depress respiratory function and exacerbate mitochondrial ROS production accelerating SkM dysfunction and aging [4]. Mice lacking Atgl show inadequate metabolic adaptations of the SkM during exercise [7]. By liberating free fatty acids, Atgl is involved in lipid signalling culminating

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