Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons
van Grootheest, G
van Meurs, JBJ
American Physiological Society
Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.
FHS gene expression profiling was funded through the Division of Intramural Research (principal investigator, Daniel Levy), National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. J. Murabito is supported by NIH Grant R01AG-029451. D. P. Kiel is supported by NIH Grant R01 AR-41398. The Framingham Heart Study is supported by NHLBI contract N01-HC-25195. The InCHIANTI study was supported in part by the Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD. D. Melzer and L. W. Harries were generously supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF). W. E. Henley was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health in England. The infrastructure for the NESDA study (http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, Grant 10-000-1002) and is supported by participating universities and mental health care organizations [VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL), and Netherlands Institute of Mental Health and Addiction (Trimbos Institute)]. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, ZonMw, the Netherlands Organisation of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The generation and management of RNA-expression array data for the Rotterdam Study were executed and funded by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Marjolein Peters, Mila Jhamai, Jeannette M. Vergeer-Drop, Bernadette van Ast-Copier, Marijn Verkerk, and Jeroen van Rooij for help in creating the RNA array expression database. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research Grants 01ZZ9603, 01ZZ0103, and 01ZZ0403; the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania; and the network Greifswald Approach to Individualized Medicine (GANI_MED) funded by the Federal Ministry of Education and Research (Grant 03IS2061A). The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens and Caché Campus program of the InterSystems.
This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record.
Vol. 48, pp. 1 - 11
Place of publication