Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC211
Sarcopenic muscle shows distinct sex differences at the transcriptional level
I. J. Gallagher1, A. J. MacDonald1, N. A. Stephens1, C. Gray2, H. Husi1, J. A. Ross1, A. Joyson3, A. Ratkevicius3, H. Wackerhage3, G. Miele4, I. Beggs5, K. C. Fearon1, C. Greig1
1. School of Clinical Sciences and Community Health, The University of Edinburgh, Edinburgh, United Kingdom. 2. Clinical Research Facility, The University of Edinburgh, Edinburgh, United Kingdom. 3. School of Medical Sciences, The University of Aberdeen, Aberdeen, United Kingdom. 4. Translational Medicine Research Collaboration Core Laboratory, The University of Dundee, Dundee, United Kingdom. 5. Department of Radiology, Royal Infirmary Edinburgh, Edinburgh, United Kingdom.
Introduction: Age-related loss of muscle mass (sarcopenia) is associated with several adverse outcomes including increased frequency of falls (Szulc et al 2005). An operational definition of sarcopenia is important in order to obtain comparable measures of prevalence, determine relative risk, target patients for therapeutic intervention, set treatment goals and monitor outcome. Current definitions of sarcopenia are based upon muscle mass referenced to young adult reference data (Cruz-Jentoft et al 2010). However no studies have attempted to validate this definition using muscle molecular biology. We hypothesised that (i) skeletal muscle gene expression would be different in the presence of sarcopenia and (ii) sex differences in the muscle transcriptomic signature would exist between elderly sarcopenic and non sarcopenic individuals. Methods: We studied 16 healthy men (n=8; mean 77 y (SD ± 0.8)) and women (n=8; 79 y (SD ± 1.2)) who were classified as sarcopenic/ non-sarcopenic on the basis of quadriceps MRI cross-sectional area (CSA) 2SD below young adult mean values for men and women (21.3 cm2.m-2 and 17.3 cm2.m-2 respectively). We obtained samples of quadriceps muscle obtained by needle biopsy (under local anaesthetic using 1% sc lignocaine). Global expression profiles were examined using Affymetrix hgu133plus2 GeneChip arrays. After non-specific filtering, the intensity of each probe was correlated with quadriceps CSA (cm2.m-2) and probes demonstrating Pearson rho > 0.5 and p-value < 0.05 were selected for further analysis (325 genes in men and 418 in women). The array data for the correlating genes were used to drive clustering of the samples by euclidean distance. We examined correlating genes in both men and women for gene ontology biological processes (GOBP) and membership of pathways (KEGG). Results: Hierarchical clustering of the array data for correlating genes revealed 2 broad clusters for both men and women around the MRI derived sarcopenia cut-off values. Informatic analysis of the correlating genes revealed marked sex differences. In men there was a strong representation for processes involved in axonogenesis and oxidative stress responses. Interestingly, the gene ontology term ‘ubiquitin mediated proteolysis’ correlated negatively with muscle CSA. In women, indicators of re-modelling (muscle tissue morphogenesis) and muscle contraction processes were strongly represented. The focal adhesion and Jak-STAT pathways were enriched. Conclusion: We have used transcriptomics to validate the operational definition of sarcopenia. Our data suggest the mechanisms underlying human sarcopenia may be different in men and women.
Where applicable, experiments conform with Society ethical requirements