Differential regulation of cysteine oxidative post-translational modifications in high and low aerobic capacity

Rodrigo W A Souza,Natale Rolim,Gustavo J J Silva,Ulrik Wisløff,Christiano R R Alves,Alessandra Medeiros,Martin Wohlwend,Animesh Sharma,Patricia C Brum,José B N Moreira,Lauren G Koch,Mohammed Gebriel,Steven L Britton,Geir Slupphaug,Marcia N Alves,Lars Hagen

doi:10.1038/s41598-018-35728-2

Abstract

Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.

Highlights

High aerobic capacity, is associated with metabolic benefits, cardiovascular protection and longevity[1,2,3,4,5]
(Table 1 and Supplemental Table 1). These data confirm that the present cohort of high-capacity runners (HCR) and Low-capacity runner (LCR) rats is an animal model of high and low intrinsic aerobic capacity
HCR rats displayed higher catalase activity than LCR rats (Fig. 3l) and unchanged protein carbonyl levels (Fig. 3m). These findings suggest that HCR rats have a modest increase in mitochondrial respiratory rate and antioxidant defense in the cardiac muscle when compared with LCR rats

Summary

Introduction

High aerobic capacity (i.e. the capacity to use oxygen), is associated with metabolic benefits, cardiovascular protection and longevity[1,2,3,4,5]. Cys Ox-PTMs may regulate cellular homeostasis in several tissues, including skeletal and cardiac muscles[13,14,15,16,17,18], but the putative relationship between Ox-PTM and intrinsic components of oxidative energy metabolism is poorly understood. In this sense, mass-spectrometry-based proteomic analysis is a powerful tool to investigate the post-translational modifications of the proteome, including Ox-PTMs18. This study provides new insights into the role of Cys Ox-PTMs as essential signals to maintain metabolic homeostasis and opens the perspective to explore Ox-PTMs to counteract metabolic diseases

Methods

Results

Conclusion