Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.

Luke C Pilling ,Carolin Malsch ,Marjolein J Peters ,Toshiko Tanaka ,Daniel Levy ,Sven Gläser ,Joyce B J Van Meurs ,Tim Kacprowski ,Joseph E Powell ,David Karasik ,Joanne M Murabito ,Reiner Biffar ,Ritsert C Jansen ,Stefania Bandinelli ,Thomas Kocher ,Luigi Ferrucci ,Andrew Singleton ,Honghuang Lin ,Brenda W J H Penninx ,Uwe Völker ,Roby Joehanes ,Albert Hofman ,William Henley ,André G Uitterlinden ,Alexander Teumer ,Lorna W Harries ,Douglas P Kiel ,Georg Homuth ,Gerard Van Grootheest ,Kathryn L Lunetta ,Peter J Munson ,Dena G Hernandez ,David Melzer

doi:10.1152/physiolgenomics.00054.2015

Abstract

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.

Highlights

IntroductionWe show that 115 genes (52%) have not previously been linked to muscle in National Center for Biotechnology Information (NCBI) PubMed abstracts
Mechanisms of complex diseases group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom; 10Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St
Of the 208 unique genes associated with muscle strength in the meta-analysis all were significant in FHS alone, and 79 (38%) were “independently” associated

Summary

Introduction

We 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. GENE TRANSCRIPTS IN BLOOD ASSOCIATED WITH MUSCLE STRENGTH needed for everyday functioning; persons with poor strength are at high risk of disability, injury from falls, and other age-related morbidities [15, 25]. Muscle strength (including grip strength) is a more important predictor of mortality risk than muscle mass [9, 32], and grip strength (but not muscle mass) was associated with poor physical functioning in older adults [51]. Current theories emphasize the role of denervation not compensated by adequate reinnervation, mitochondrial dysfunction, cellular senescence, inflammation, changes in microenvironment, and local skeletal changes, among other factors [4, 44]

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