Abstract 339: Endogenous Muscle Atrophy F-box is a Positive Mediator of Cardiac Hypertrophy and Dysfunction in Response to Pressure Overload
Muscle atrophy F-box (MAFbx, Atrogin-1) is an E3 ubiquitin ligase which plays a critical role in mediating skeletal muscle atrophy. It has been shown that cardiac specific expression of MAFbx inhibits pressure overload-induced cardiac hypertrophy, suggesting that MAFbx negatively regulates cardiac mass when overexpressed. To elucidate the role of endogenous MAFbx in regulating cardiac mass, we applied transverse aortic constriction (TAC) to MAFbx −/− and wild type (WT) mice. Pressure gradients in both groups were comparable (MAFbx −/− 90.4 mmHg vs WT 79.3 mmHg). In WT mice, protein expression of MAFbx in the heart was significantly increased (3.5 fold) after 2 weeks of TAC. Unexpectedly, left ventricular weight/body weight (LVW/BW) was significantly smaller in MAFbx −/− than in WT mice (4.49 vs 5.58, p < 0.01). The echocardiographically determined LV posterior wall thickness (1.00 vs 1.13 mm, p < 0.05) and LV mass index (151 vs 193, p < 0.05) after TAC were significantly smaller in MAFbx −/− than in WT mice, consistent with the notion that MAFbx −/− mice develop less hypertrophy in response to TAC. Lung weight/BW after TAC was significantly increased compared with the sham operated group in WT (10.1 vs 5.1, p < 0.01) but not in MAFbx −/− mice (6.0 vs 4.9, NS), suggesting that LV dysfunction after TAC was inhibited in MAFbx −/− mice. Furthermore, picric acid-Sirius red staining revealed that there was significantly less interstitial fibrosis after TAC in MAFbx −/− than in WT mice. These results suggest that MAFbx is up-regulated in response to pressure overload, and that the absence of endogenous MAFbx decreases hypertrophy and interstitial fibrosis and maintains cardiac function. In conclusion, distinct from its essential role in skeletal muscle atrophy, and also in direct contrast to the results seen with mice overexpressing MAFbx, endogenous MAFbx in the heart promotes cardiac hypertrophy and dysfunction during pressure overload.