Abstract
BackgroundAlthough high-throughput studies of gene expression have generated large amounts of data, most of which is freely available in public archives, the use of this valuable resource is limited by computational complications and non-homogenous annotation. To address these issues, we have performed a complete re-annotation of public microarray data from human skeletal muscle biopsies and constructed a muscle expression compendium consisting of nearly 3000 samples. The created muscle compendium is a publicly available resource including all curated annotation. Using this data set, we aimed to elucidate the molecular mechanism of muscle aging and to describe how physical exercise may alleviate negative physiological effects.ResultsWe find 957 genes to be significantly associated with aging (p < 0.05, FDR = 5 %, n = 361). Aging was associated with perturbation of many central metabolic pathways like mitochondrial function including reduced expression of genes in the ATP synthase, NADH dehydrogenase, cytochrome C reductase and oxidase complexes, as well as in glucose and pyruvate processing. Among the genes with the strongest association with aging were H3 histone, family 3B (H3F3B, p = 3.4 × 10−13), AHNAK nucleoprotein, desmoyokin (AHNAK, p = 6.9 × 10−12), and histone deacetylase 4 (HDAC4, p = 4.0 × 10−9). We also discover genes previously not linked to muscle aging and metabolism, such as fasciculation and elongation protein zeta 2 (FEZ2, p = 2.8 × 10−8). Out of the 957 genes associated with aging, 21 (p < 0.001, false discovery rate = 5 %, n = 116) were also associated with maximal oxygen consumption (VO2MAX). Strikingly, 20 out of those 21 genes are regulated in opposite direction when comparing increasing age with increasing VO2MAX.ConclusionsThese results support that mitochondrial dysfunction is a major age-related factor and also highlight the beneficial effects of maintaining a high physical capacity for prevention of age-related sarcopenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-015-0059-1) contains supplementary material, which is available to authorized users.
Highlights
High-throughput studies of gene expression have generated large amounts of data, most of which is freely available in public archives, the use of this valuable resource is limited by computational complications and non-homogenous annotation
Reduced expression of genes in the oxidative phosphorylation (OXPHOS) pathway, including the regulator peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α), has been found to be reduced in skeletal muscle from type 2 diabetic patients [9, 10], a strongly age-related metabolic disorder. Another central pathway previously associated with muscle aging is the mammalian target of rapamycin, including the mTOR complex I which plays a crucial role in the regulation of translation in skeletal muscle [11]
Reuse of public data is hampered by the use of different experimental platforms and sample annotation, and analysis is not straightforward when combining such data [17]. Based on this muscle expression compendium, we present the largest study to date of gene expression in human skeletal muscle related to aging
Summary
High-throughput studies of gene expression have generated large amounts of data, most of which is freely available in public archives, the use of this valuable resource is limited by computational complications and non-homogenous annotation To address these issues, we have performed a complete re-annotation of public microarray data from human skeletal muscle biopsies and constructed a muscle expression compendium consisting of nearly 3000 samples. De Magalhaes and colleagues [6] conducted a metaanalysis of microarray experiments on aging in mice, rats, and humans across a variety of tissues In this crossspecies, cross-platform analysis, gene orthologues were meta-analyzed for approximately 400 samples, 42 of which were from human skeletal muscle, comparing old to young individuals. Reduced expression of genes in the OXPHOS pathway, including the regulator peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α), has been found to be reduced in skeletal muscle from type 2 diabetic patients [9, 10], a strongly age-related metabolic disorder. A metabolic link between mTOR and glycolysis has been described where low glycolytic flux leads to binding of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to the mTORC1-regulator Rheb thereby inhibiting mTORC1 signaling and suppression of protein synthesis [12]
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