Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity

Alexander V Chibalin,Amy E Mendham,Cindy George,Steen Larsen,Melony C Fortuin-De Smidt,Jon Hauksson,Julia H Goedecke,Elin Chorell,Yingxu Zeng,Tommy Olsson

doi:10.1007/s00125-021-05430-6

Abstract

Aims/hypothesisWe sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity.MethodsThis study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting.ResultsThe original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0–4.6] to 3.6 [2.4–6.2] x10−5 pmol l−1 min−1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg−1 min−1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p < 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p < 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p < 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p < 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p < 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2.Conclusions/interpretationThe major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes.Graphical abstract

Highlights

Low levels of physical activity and cardiorespiratory fitness are two components contributing to the increasing rates of obesity [1]
The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, which were associated with content-driven increases in mitochondrial respiration, and not whole-body insulin sensitivity
We propose that improved mitochondrial respiratory capacity and content in response to exercise training alters specific phospholipids, DAGs and ceramide, independent of the improvements in insulin sensitivity and GLUT4 protein expression (Fig. 9)

Summary

Introduction

Low levels of physical activity and cardiorespiratory fitness are two components contributing to the increasing rates of obesity [1]. Reduced mitochondrial respiratory capacity with reduced lipid utilisation can lead to the accumulation of ‘toxic’ lipid intermediates in skeletal muscle, which may be key to the development of insulin resistance and type 2 diabetes [2, 4, 5]. Putative influences of mitochondrial biogenesis and whole-body insulin sensitivity on skeletal muscle lipid intermediates may play important roles [8, 12–14]. Lipid intermediates such as diacylglycerols (DAGs) and ceramides are considered ‘lipotoxic’ and contribute to muscle insulin resistance [7, 8]. Both DAGs and ceramides may block important enzymatic pathways that affect the muscle’s responsiveness to insulin [6, 15]. Similar to DAGs, ceramides’ biological activity and ability to induce organ/organelle dysfunction lies in their localisation and acyl composition [10]

Methods

Results

Conclusion