| Steroid hormones are small lipophilic compounds synthesized from cholesterol and are important for numerous physiological and hormonal functions. This dissertation is focused on the effects of two types of steroid hormones, estrogens and glucocorticoids, on skeletal muscle. The first part of this dissertation investigates estrogen effects on skeletal muscle growth at the molecular level. Previous work suggested estrogen limits skeletal muscle growth in ovariectomized (OVX) rats. The underlying mechanisms were further investigated by monitoring specific muscle growth factors, myostatin and insulin-like growth factor-1 (IGF-1), following estrogen administration in the OVX rats. The mRNA and protein expression of both growth factors were measured at the end of 1 week or 5 weeks of treatments. Myostatin protein was found to increase with 1-week estrogen treatment only in the slow muscle (soleus, SOL), while IGF-1 protein was universally down-regulated by estrogen in the fast (extensor digitorum longus, EDL), slow, and mixed (gastrocnemius, GAS) muscles. Discordance between the mRNA and protein of both growth factors was observed. There was no treatment effect on IGF-1 and myostatin expression in the 5 week study suggesting a transient estrogen effect or up-regulation of a compensatory mechanism to counteract the estrogen effect observed at the earlier time point (1 week). The second part was to elucidate a better understanding of the potential underlying mechanism(s) of glucocorticoid-induced muscle atrophy. Gene array technology (Affymetrix) was employed to study multiple genes simultaneously. Glucocorticoid treatment was found to affect some of the ubiquitin-conjugases (E2 enzymes) and the ubiquitin-ligases (E3 enzymes) in the UPS pathway. A mechanism-based PK/PD modeling on the E3 enzymes, namely MuRF-1 and Atrogin-1, was conducted. The proposed model captured the acute data well; however, the model predicted an elevated expression throughout the chronic study and as such, did not capture the last time point (168 hour) where the gene expression had returned to the baseline. The results suggested the current understanding of the glucocorticoid receptor mechanism is not sufficient in describing the genomic response in skeletal muscle. A compensatory mechanism in addition to the down-regulation of the glucocorticoid receptor may exist and together they govern glucocorticoid resistance. |
