title: Global gene expression profiles in skeletal muscle of monozygotic female twins discordant for hormone replacement therapy.
abstract: Aging is accompanied by inexorable loss of muscle tissue. One of the underlying causes for this is the massive change in the hormonal milieu of the body. The role of a female sex steroid - estrogen - in these processes is frequently neglected, although the rapid decline in its production coincides with a steep deterioration in muscle performance. We recruited 54- to 62-year-old monozygotic female twin pairs discordant for postmenopausal hormone replacement therapy (HRT, n=11 pairs; HRT use 7.3 ± 3.7 years) from the Finnish Twin Cohort to investigate the association of long-term, estrogen-based HRT with skeletal muscle transcriptome. Pathway analysis of muscle transcript profiles revealed significant HRT-induced up-regulation of a biological process related to regulation of cell structure and down-regulation of processes concerning, for example, cell-matrix interactions, energy metabolism and utilization of nutrients (false discovery rate < 0.15). Lending clinical relevance to the findings, these processes explained a significant fraction of the differences observed in relative proportion of muscle within thigh and in muscle performance (R(2) =0.180-0.257, P=0.001-0.023). Although energy metabolism was affected through down-regulation of the transcripts related to succinate dehydrogenase complex in mitochondria, no differences were observed in mtDNA copy number or oxidative capacity per muscle cross section. In conclusion, long-term use of HRT was associated with subtle, but significant, differences in muscle transcript profiles. The better muscle composition and performance among the HRT users appeared to be orchestrated by improved regulatory actions on cytoskeleton, preservation of muscle quality via regulation of intramuscular extracellular matrix and a switch from glucose-oriented metabolism to utilization of fatty acids.
authors.affiliation: Department of Health Sciences, University of Jyväskylä, PO Box 35, FIN-40014 Jyväskylä, Finland.
authors.forename: Paula H A
authors.initials: PH
authors.lastname: Ronkainen
authors.forename: Eija
authors.initials: E
authors.lastname: Pöllänen
authors.forename: Markku
authors.initials: M
authors.lastname: Alén
authors.forename: Reino
authors.initials: R
authors.lastname: Pitkänen
authors.forename: Jukka
authors.initials: J
authors.lastname: Puolakka
authors.forename: Urho M
authors.initials: UM
authors.lastname: Kujala
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Sarianna
authors.initials: S
authors.lastname: Sipilä
authors.forename: Vuokko
authors.initials: V
authors.lastname: Kovanen
mesh_terms: D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics; D015536:Down-Regulation; D015914:Estrogen Replacement Therapy / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D013385:Succinate Dehydrogenase