Abstract 395: Muscle Ring Finger-2 (MuRF2), Implicated in M-Line Mechano-Sensing, does not Modulate Cardiac Hypertrophy in vivo
To meet the demands of an ever changing environment, the heart appropriately responds to stress by detecting mechanical stretch. This is a particularly important mechanism in cardiac hypertrophy whereby an increased afterload is recognized, specific gene transcription is initiated, resulting in the necessary increase in muscle mass. To date, mechano-sensing pathways have involved integrins and signaling pathways linked to the Z-disk. Recently, a novel mechano-sensing apparatus was described at the M line (Science 308:1599, 2005). In this model, the giant protein titin senses mechanical pull, and signals through its M line kinase domain. Subsequently, interaction with multiple scaffold proteins (nbr1, p62) and MuRF2 was found, which interacts directly to modulate SRF, a key transcription factor in the induction of cardiac hypertrophy. To determine if this M-line mechano-sensing pathway involving the titin-kinase-nbr1-p62-MuRF2 complex plays a role in the development of cardiac hypertrophy, we performed trans-aortic banding (TAC) in mice lacking the MuRF2 gene (MuRF2−/−) and their wild type siblings (MuRF2 +/+). We then followed the function and wall thickness over time by echocardiography for 4 weeks. At baseline, no detectable difference in anterior (1.2±0.04 mm vs. 1.19±0.12 mm) or posterior wall (1.18±0.04 mm vs. 1.1±0.02 mm) thicknesses or function (FS% 45.1±6.4% vs. 49±5.4%) in MuRF2 −/− mice compared to wild type controls was present. Four weeks after TAC, a robust cardiac hypertrophy was identified in both MuRF2 −/− and MuRF2 +/+ mice that was not significantly different between the groups as detected by echocardiography (In diastole: anterior wall 1.48±0.15 mm vs. 1.6±0.14 mm; posterior wall 2.2±0.10 mm vs. 2.1±0.12 mm). Similarly, the left ventricular mass was not different 4 weeks post-TAC between the two groups (209.8±27.9 mg vs. 251±45.8 mg). When we determined the MuRF2 mRNA levels after TAC, we found that cardiac levels did not change significantly from baseline levels over time. These findings suggest for the first time that the proposed M-line mechano-sensing apparatus may not have a role in the process of cardiac hypertrophy induction, despite the intriguing connection between mechano-sensing and MuRF2’s ability to interact with SRF.