Abstract 16700: MURC, Muscle-Restricted Coiled-Coil Protein, Regulates Caveolae Morphology and Induces Hypertrophy in Cardiomyocytes
Background: We have cloned and characterized MURC, muscle-restricted coiled-coil protein, which is localized to the cytoplasm with accumulation in the Z-line of striated muscle. Transgenic mice expressing MURC (Tg-MURC) in the heart show cardiomyocyte (CM) hypertrophy and subsequently exhibit contractile dysfunction. MURC shares structural PEST (proline, glutamic acid, serine, and threonine-rich) domains with cavin family members which regulate caveolae morphology. Caveolae is implicated in many cellular processes including cell signaling and transport, and caveolin-3 is required for caveolae formation in CMs. However, the role of MURC in caveolae morphology and signaling pathways responsible for MURC-induced CM hypertrophy remain to be determined.
Methods and Results: To elucidate the molecular mechanism involving MURC, we performed the affinity purification and mass spectrometric analyses. In this screen, we identified polymerase I and transcript release factor (PTRF)/cavin-1 as one of MURC-binding proteins. PTRF/cavin-1, serum deprivation protein response (SDPR)/cavin-2, and SDR-related gene product that binds to C kinase (SRBC)/cavin-3 were expressed both in CMs and non-CMs. We also found that MURC bound to SDPR/cavin-2 and caveolin-3, which is the muscle-specific isoform of caveolin, and that SDPR/cavin-2 bound to caveolin-3. Immunostaining revealed that MURC was co-localized with caveolin-3 at plasma membrane caveolae of CMs. When MURC was overexpressed in CMs, formation of distended caveolae, activation of extracellular signal-regulated kinase (ERK), and increases in cell size were induced. In Dahl salt-sensitive rats, MURC mRNA expression was up-regulated both in hypertrophied and failed hearts. ERK activation was induced in the hypertrophic phase of Tg-MURC mouse hearts. In CMs, RNAi-mediated knockdown of MURC impaired phenylephrine-induced increases in cell size and ERK activation. Furthermore, MURC-induced BNP mRNA expression and increases in cell size were attenuated by a MEK inhibitor in a dose-dependent manner.
Conclusion: These findings indicate that MURC is a component of the caveolin-cavin complex and regulates caveolae morphology, and that MURC utilizes the ERK pathway to induce CM hypertrophy.
- © 2010 by American Heart Association, Inc.