Muscle RING finger‐1 (MuRF1) inhibits thyroid receptorα transcriptional activity and thyroid hormone‐dependent cardiac hypertrophy

Abstract

We previously identified that MuRF1 regulates PPARα transcriptional activity in cardiomyocytes by post‐translationally modifying the protein with ubiquitin. To determine if MuRF1 has a broader role in regulating nuclear receptors, we determined MuRF1's effect on thyroid receptor‐α(TRα) activity, the predominant TR subtype in the heart. Using thyroid receptor response element (TRE)‐driven luciferase assays, we found that MuRF1 significantly inhibited triiodothyronine (T3)‐dependent increases in TRα activity. To explore the physiological significance of MuRF1's inhibition of TRα activity, we challenged MuRF1 −/− and MuRF1 transgenic (with cardiac‐specific overexpression) to daily T3 treatment (1 mg/kg/day) for 14 days and followed the heart by echocardiography at baseline, 7 days, and 14 days. After 14 days of T3 treatment, MuRF1−/− animals exhibited a 90.9% increase in LV mass over baseline, while wildtype littermates showed only a 58.9% increase in LV mass over baseline. Conversely, MuRF1 Tg mice showed a 44.4% increase in LV mass over baseline compared to the 73.0% increase in LV mass over baseline exhibited by wildtype littermates. These results suggest MuRF1 inhibits thyroid hormone‐dependent cardiac growth governed, at least in part, by MuRF1's ability to directly interact with TRα, inhibiting its transcriptional activity likely by post‐translational modification with ubiquitin.