A novel atlas of gene expression in human skeletal muscle reveals molecular changes associated with aging

Jing Su, Carl Ekman, Nikolay Oskolkov, Leo Lahti, Kristoffer Ström, Alvis Brazma, Leif Groop, Johan Rung, Ola Hansson, Jing Su, Carl Ekman, Nikolay Oskolkov, Leo Lahti, Kristoffer Ström, Alvis Brazma, Leif Groop, Johan Rung, Ola Hansson

Abstract

Background: Although 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.

Results: We 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.

Conclusions: These 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.

Keywords: Aging; Exercise; Expression; Microarray; Mitochondrial dysfunction; Skeletal muscle.

Figures

Fig. 1
Fig. 1
Principal component analysis of the 211 HG-U133A arrays, before (a) and after (b) removal of study effects and corresponding plots for the 150 HG-U133 + 2 arrays (c and d). Different studies (identified by database accession numbers) are represented with different colors, and increasing age of the individual from whom the biopsy was taken is indicated by the increasing dot size. The relatively strong study effect seen even after normalization is removed after the adjustment
Fig. 2
Fig. 2
Expression levels of SOCS2 (a), FEZ2 (b), MPC1 (c), and NT5C2 (d) in relation to age. Batch effect-adjusted expression levels are shown
Fig. 3
Fig. 3
Schematic illustration of major metabolic effects of aging in human skeletal muscle. A subjectively selected set of effector and regulatory genes from the 957 age-associated genes are shown with their direction of regulation shown with respect to increasing age

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