Identification of a molecular signature of sarcopenia

Abstract

Investigating the molecular mechanisms underlying sarcopenia in humans with the use of microarrays has been complicated by low sample size and the variability inherent in human gene expression profiles. We have conducted a study using Affymetrix GeneChips to identify a molecular signature of aged skeletal muscle. The molecular signature was defined as the set of expressed genes that best distinguished the vastus lateralis muscle of young ( n = 10) and older ( n = 12) male subjects, when a k-nearest neighbor supervised classification method was used in conjunction with a signal-to-noise ratio gene selection method and a holdout cross-validation procedure. The age-specific expression signature was comprised of 45 genes; 27 were upregulated and 18 were downregulated. This signature also correctly classified 75% of the muscle samples from young and older subjects published by an independent laboratory, based on their expression profiles. The signature revealed increased expression of several genes involved in mediating cellular responses to inflammation and apoptosis, including complement component C1QA, Galectin-1, C/EBP-β, and FOXO3A, among others. The increased expressions of genes that regulate pre-mRNA splicing, localization, and modification of RNA comprise markers of the aging signature. Downregulated genes in the signature were the glutamine transporter SLC38A1, a TRAF-6 inhibitory zinc finger protein, and membrane-bound transcription factor protease S2P, among others. The sarcopenia signature developed here will be useful as a molecular model to judge the effectiveness of exercise and other therapeutic treatments aimed at ameliorating the effects of muscle loss associated with aging.

Muscular Transcriptome in Postmenopausal Women With or Without Hormone Replacement

“…52 These studies suggest that the association between Atrogin-1 and muscle atrophy may be fiber type-or gender-dependent. Another explanation could be that sarcopenia is mechanistically different from acute muscle atrophy, which is marked by increased expression of Atrogin-1, as suggested by Edstrom et al 51 This statement is supported by the findings of Giresi and colleagues, 45 who conducted a microarray study with muscle samples from 19-25-yr-old and 70-80-yr-old male subjects to identify the molecular signature of sarcopenia.…”

“…High density oligonucleotide microarrays have previously been utilized to characterize, e.g., age-or exercise-related changes in human skeletal muscle, [40][41][42][43][44][45][46][47][48][49] but not directly menopause-or HRT-related transcriptional changes. The transcriptome-wide effects of HRT have only been studied in blood samples from postmenopausal women.…”

“…However, similar 41,43,45,47,63 or even smaller 40,42,44,46,48 numbers of subjects have been successfully utilized in previous microarray studies investigating transcriptional changes in skeletal muscle. In our study, an extra strength is achieved by using RCT-design with repeatedmeasures analysis, which enables the detection of intra-individual changes in gene expression.…”

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…Transcriptional networks altered with aging have been well characterized (Giresi et al ., 2005); however, whether global changes in the expression of genes related to muscle regeneration play a causative or compensatory role in age‐related defective muscle regeneration remains an unanswered question.…”

Modifying muscle mass – the endocrine perspective

“…A recent report using microarray analysis comparing muscle biopsies in 10 young versus 12 older subjects found that muscle from older subjects demonstrated differences associated with apoptosis, such as increased complement component C1QA, galectin-1, C/EBP-b and FOXO-3A expression -findings considered as a 'molecular signature' of sarcopenia (Giresi et al 2005). A decline in anabolic hormones and reduction in myonuclei via apoptotic-like mechanisms represent alternative explanations for sarcopenia (Leeuwenburgh 2003).…”