Physiological Thyroid Hormone Levels Regulate Numerous Skeletal Muscle Transcripts

Abstract

Context: Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels. Objective: We examined the effects of l-thyroxine on human skeletal muscle transcriptome. Design: Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. Setting: The study was conducted in a university hospital laboratory. Patients: We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off l-thyroxine replacement. Mean Outcome Measures: Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods. Results: We detected 607 differentially expressed genes on l-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. l-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b. Conclusion: We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes. Skeletal muscle has a major contribution to the metabolic rate in humans; data demonstrate that skeletal muscle transcriptome is largely changed in different thyroid states.