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Skeletal muscle gene expression in twin-pairs discordant for their physical activity for over 30 years

ABSTRACT: The high physical activity/high aerobic fitness phenotype predicts low morbidity and mortality more strongly than any other known biological risk factor. Inherited and/or acquired properties of skeletal muscle seem to be linked with aerobic fitness and other cardio-metabolic risk factors3. However, physical activity-induced changes in muscle and fat tissue-related complex molecular networks and their links with cardio-metabolic disease risk are not comprehensively understood. Here we show that among the physically active members of twin pairs, as compared to their inactive co-twins, gene expression in musculus vastus lateralis tissue samples is chronically up-regulated for the central pathways or genes related to energy metabolism, including oxidative phosphorylation, lipid metabolism and supportive metabolic pathways. In addition to aerobic fitness, upregulation of these pathways is associated in particular with high HDL cholesterol levels. In fat tissue we found physical activity-induced increases in polyunsaturated fatty acid metabolism and in branched chain amino acid degradation, which increases were associated with decreased ‘high-risk’ ectopic body fat and low glucose levels. Consistent with other findings plasma lipidomics analyses showed up-regulation of the triacylglycerols containing the polyunsaturated fatty acids. The findings indicate the main pathways in skeletal muscle and fat tissue that mediate the chronic effects of physical activity on reduced cardio-metabolic disease risk, including the increase in aerobic fitness. Up-regulation of oxidative energy metabolism seems to be a common underlying mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20319 | GEO | 2010/07/31

SECONDARY ACCESSION(S): PRJNA125377

REPOSITORIES: GEO

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Project description:Epidemiological studies reveal a strong link between low aerobic capacity and metabolic and cardiovascular diseases. Two-way artificial selection of rats based on low and high intrinsic exercise capacity has produced two strains that also differ in risk for metabolic syndrome (Koch LG, Britton SL. Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol Genomics 5:45-52, 2001). Here we investigated skeletal muscle characteristics and genotype-phenotype relationships behind high and low inherited aerobic exercise capacity and the link between oxygen metabolism and metabolic disease risk factors in rats derived from generation 18. This population (n=24) of high capacity runners (HCR) and low capacity runners (LCR) differed by 615% in maximal treadmill running capacity. LCR were significantly significantly heavier and had increased blood glucose, serum insulin and triglyceride concentration. HCR had higher resting metabolic rate than LCR. Capillaries/mm2 and capillary-to-fiber ratio were significantly greater in HCR rats in soleus and gastrocnemius and capillary-to-fiber ratio in extensor digitorum longus (EDL) muscle. Subsarcolemmal mitochondrial area was 96% (p<0.01) and intermyofibrillar area was 32% (p<0.05) larger in HCR soleus. Microarray results showed that 126 genes were significantly up-regulated and 113 genes were down-regulated in HCR (p<0.05). Functional clustering and unbiased correlation analysis of muscle microarray data revealed that genes up-regulated in HCR were related to mitochondria, carboxylic acid and lipid metabolism, and oxidoreductase activity. In conclusion, our data show that aerobic capacity is strongly linked to the architecture of energy transfer and corroborate the importance of oxygen metabolism as the determinant of metabolic health and complex metabolic diseases such as metabolic syndrome and type 2 diabetes. Total RNA obtained from gastrocnemius muscle was compared between rat strains of low and high inherited aerobic exercise capacity.

Project description:This study used untargeted proteomics to compare blood proteomic profiles in two groups of adults that differed widely in lifestyle habits. The goal was to identify a core list of proteins that were either upregulated or downregulated based on adherence to recommended lifestyle habits in adults. A total of 52 subjects in the lifestyle group (LIFE) (28 males, 24 females) and 52 in the control group (CON) (27 males, 25 females) participated in this cross-sectional study. Age, education level, marital status, and height did not differ significantly between LIFE and CON groups. The LIFE and CON groups differed markedly in body composition and fat mass-related anthropometric measurements including waist circumference, body mass index (BMI), sagittal abdominal diameter (SAD), and body composition (body fat percentage and fat mass index or FMI) (p<0.001). LIFE and CON groups were also widely disparate in physical activity patterns and maximal aerobic fitness, dietary intake patterns, disease risk factor prevalence, blood measures of inflammation, triglycerides, HDL-cholesterol, glucose, and insulin, weight-adjusted leg/back and handgrip strength, and mood states. The proteomics analysis showed strong group differences for 39 of 725 proteins identified in the dried blood spot samples. Of these, 18 were downregulated in the LIFE group and collectively indicated a lower innate immune activation signature. A total of 21 proteins were upregulated in the LIFE group and supported greater lipoprotein metabolism and HDL remodeling. Lifestyle-related habits and biomarkers were probed and the variance (>50%) in downregulated and upregulated proteins was best explained by group contrasts in indicators of body composition and visceral fat including FMI and SAD. This cross-sectional study established that a relatively small number of upregulated and downregulated proteins are associated with good lifestyle habits. A targeted “lifestyle” proteomic panel based on these data could be used in future studies to determine the efficacy of various prevention and treatment strategies.

Project description:Purpose: Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and soleus gene expression we examined genome-wide gene expression in soleus muscle of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in man, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in the two groups, since accumulating evidence indicates that exercise has profound beneficial effects on the metabolic syndrome. Methods:; Soleus gene expression of both sedentary and exercise trained HCR and LCR was characterized by microarray- and gene ontology analysis. Results: Although HCR and LCR had an inborn 347% difference in running capacity, only three genes were found differentially expressed in the soleus muscle between the two groups. Up-regulation of the mitochondrial enzyme leucyl-transferRNA synthetase (LARS2) was found in the sedentary LCR. Increased expression of LARS2 has been associated with a mitochondrial DNA mutation linked to maternally inherited diabetes and mitochondrial dysfunction. In line with our findings, a growing body of evidence suggests that LCR have compromised mitochondrial function. After exercise training, 58 genes were altered in the soleus muscle of HCR, in contrast to only one in the LCR group. This suggests that animals born with different levels of fitness respond different to the same type of exercise training. Adaptations to exercise in HCR seemed to be associated with increased lipid metabolism and fatty acid elongation in the mitochondria. Also, genes associated with the peroxisomes, seemed to be central in the adaptation to exercise. Conclusion: The results indicate that (i) LCR might have mitochondrial dysfunction, which may be a contributing factor of the low inborn aerobic capacity, (ii) animals born with different levels of fitness respond different to the same exercise program. Experiment Overall Design: There are 16 samples in this study.

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Skeletal muscle gene expression in twin-pairs discordant for their physical activity for over 30 years

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