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Aging Cell. 2018 Feb;17(1). doi: 10.1111/acel.12700. Epub 2017 Nov 9.

Running-wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post-transcriptional mechanism.

Author information

1
Section Systems Medicine of Metabolism and Signaling, Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
2
Systems Biology Centre for Energy Metabolism and Ageing, University of Groningen, Groningen, The Netherlands.
3
Department of Behavioral Neuroscience, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands.
4
Department of Pharmacy, Analytical Biochemistry, University of Groningen, Groningen, The Netherlands.
5
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
6
Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
7
Department of Vascular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands.
8
Centre for Isotope Research, University of Groningen, Groningen, The Netherlands.

Abstract

Loss of mitochondrial respiratory flux is a hallmark of skeletal muscle aging, contributing to a progressive decline of muscle strength. Endurance exercise alleviates the decrease in respiratory flux, both in humans and in rodents. Here, we dissect the underlying mechanism of mitochondrial flux decline by integrated analysis of the molecular network. Mice were given a lifelong ad libitum low-fat or high-fat sucrose diet and were further divided into sedentary and running-wheel groups. At 6, 12, 18 and 24 months, muscle weight, triglyceride content and mitochondrial respiratory flux were analysed. Subsequently, transcriptome was measured by RNA-Seq and proteome by targeted LC-MS/MS analysis with 13 C-labelled standards. In the sedentary groups, mitochondrial respiratory flux declined with age. Voluntary running protected the mitochondrial respiratory flux until 18 months of age. Beyond this time point, all groups converged. Regulation Analysis of flux, proteome and transcriptome showed that the decline of flux was equally regulated at the proteomic and at the metabolic level, while regulation at the transcriptional level was marginal. Proteomic regulation was most prominent at the beginning and at the end of the pathway, namely at the pyruvate dehydrogenase complex and at the synthesis and transport of ATP. Further proteomic regulation was scattered across the entire pathway, revealing an effective multisite regulation. Finally, reactions regulated at the protein level were highly overlapping between the four experimental groups, suggesting a common, post-transcriptional mechanism of muscle aging.

KEYWORDS:

Regulation Analysis; integrative data analysis; metabolism; mitochondrial function; skeletal muscle aging; targeted proteomics

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