Muscle Ring Finger‐1 (MuRF1), MuRF2, and MuRF3 Differentially Regulate the transcription factors PPARα, PPARγ, and PPARβ/δ, respectively, in vivo

The ubiquitin ligase Muscle Ring Finger‐1 (MuRF1) plays a key role in regulating PPARα mediated fatty acid and glucose oxidation in cardiomyocytes. Since the closely related MuRF2 and MuRF3 proteins have redundant activity experimentally, we determined their regulation of PPARα, PPARβ/δ, and PPARγ in the intact heart. Cardiomyocyte PPAR activity was assayed by isolating fresh nuclei from MuRF1 −/−, MuRF2 −/−, and MuRF3 −/− mouse hearts as well at MuRF1 Tg+ hearts. Compared to sibling‐matched controls, MuRF1 Tg+ hearts exhibited significantly less PPARα activity (42.7+/−7.7%, p=.004). MuRF1 Tg+ hearts did not have significantly different PPARβ/δ or PPARγ activities in vivo , consistent with our in vitro findings. Consistent with MuRF1's inhibitory activity on PPARα, MuRF1−/− hearts demonstrated a 5 fold increase (p<0.001) in PPARα activity; no differences in PPARβ/δ, or PPARγ were identified. Alternatively, MuRF2−/− hearts had the most prominent increase in PPARγ activity (4 fold increase, p<0.001), while MuRF3−/− hearts had the most prominent increase in PPARβ/δ (3 fold increase, p<0.001). These findings demonstrate for the first time that cardiac MuRF1, MuRF2, and MuRF3 specifically regulate the PPARα, PPARγ, and PPARβ/δ, respectively, in vivo , and indicate a significant and non‐redundant role of MuRF family proteins in cardiac energy metabolism. Supported by NIH R01HL104129.