Differences in muscle and adipose tissue gene expression and cardio-metabolic risk factors in the members of physical activity discordant twin pairs

Abstract

High physical activity/aerobic fitness predicts low morbidity and mortality. Our aim was to identify the most up-regulated gene sets related to long-term physical activity vs. inactivity in skeletal muscle and adipose tissues and to obtain further information about their link with cardio-metabolic risk factors. We studied ten same-sex twin pairs (age range 50-74 years) who had been discordant for leisure-time physical activity for 30 years. The examinations included biopsies from m. vastus lateralis and abdominal subcutaneous adipose tissue. RNA was analyzed with the genome-wide Illumina Human WG-6 v3.0 Expression BeadChip. For pathway analysis we used Gene Set Enrichment Analysis utilizing active vs. inactive co-twin gene expression ratios. Our findings showed that among the physically active members of twin pairs, as compared to their inactive co-twins, gene expression in the muscle tissue samples was chronically up-regulated for the central pathways related to energy metabolism, including oxidative phosphorylation, lipid metabolism and supportive metabolic pathways. Up-regulation of these pathways was associated in particular with aerobic fitness and high HDL cholesterol levels. In fat tissue we found physical activity-associated increases in the expression of polyunsaturated fatty acid metabolism and branched-chain amino acid degradation gene sets both of which associated with decreased 'high-risk' ectopic body fat and plasma glucose levels. Consistent with other findings, plasma lipidomics analysis showed up-regulation of the triacylglycerols containing the polyunsaturated fatty acids. Our findings identified skeletal muscle and fat tissue pathways which are associated with the long-term physical activity and reduced cardio-metabolic disease risk, including increased aerobic fitness. In particular, improved skeletal muscle oxidative energy and lipid metabolism as well as changes in adipocyte function and redistribution of body fat are associated with reduced cardio-metabolic risk.

Figure 1. Follow-up physical activity discordance in the 10 twin pairs.

Data is Mean ± SD. Calculation of mean MET discordance was based on a series of structured questions on leisure time physical activity and was quantified by calculation of the leisure activity metabolic equivalent [intensity x duration x frequency] expressed as a sum score of leisure time MET hours/day , .

Figure 2. Up-regulated gene sets in muscle and fat tissue and their association with cardio-metabolic risk.

Among the physically active members of twin pairs, as compared to their inactive co-twins, gene expression in the skeletal muscle was up-regulated for the central pathways of energy metabolism and supportive metabolic pathways related especially to the processes of oxidative energy production. In fat tissue the pathways were related e.g. to branched-chain amino acid degradation and PUFA synthesis. These metabolic changes were associated with decreased cardio-metabolic risk, including an increase in aerobic fitness. Centroids: OXPHOS, Oxidative phosphorylation; VLI deg, Valine, leucine and isoleucine degradation; CoQ, Ubiquinone biosynthesis; PRO met, Propanoate metabolism; FA metab, Fatty acid metabolism including mitochondrial β-oxidation and peroxisomal β-oxidation; BUT met, Butanoate metabolism; TRP met, Tryptophan metabolism; F-M met, Fructose and mannose metabolism; CAA deg, Chloroacrylic acid degradation; Urea cycle, Urea cycle and metabolism of amino groups; IL2RB, IL2RB pathway; PUFA syn, Polyunsaturated fatty acid biosynthesis; RECK, RECK pathway; PGA syn, Prostaglandin synthesis regulation; T Cytotox, T cytotoxic pathway.