Muscle ring finger 1 mediates cardiac atrophy in vivo

Abstract

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1(-/-) mice decreased approximately 70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by beta-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1(-/-) and wild-type hearts after TAC release. In the second model, MuRF1(-/-) mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.

Cardiac proteasome activity in muscle ring finger-1 null mice at rest and following synthetic glucocorticoid treatment

“…The response of 6-mo-old WT and MuRF1 KO hearts to 28 days of Dex treatment was opposite to that previously reported (51). Therefore, we examined the response of WT and MuRF1 KO hearts from 4-mo-old mice to 14 days of Dex treatment.…”

“…Skeletal muscle mass is spared in mice lacking MuRF1 following certain atrophyinducing conditions (4,34). With respect to the heart, the genetic deletion of MuRF1 alone has not been shown to lead to any significant alterations in cardiac mass or function at rest but has been shown to induce greater hypertrophy in response to transaortic banding (51). In contrast, deletions of MuRF1 and either MuRF2 or MuRF3 lead to significant cardiac hypertrophy (19,52).…”

The ubiquitin proteasome system in human cardiomyopathies and heart failure

“…Increased E1 (9,96) and E2 protein (38,96), ubiquitin mRNA (38), and ubiquitin carboxyl-terminal hydrolase mRNA (96) and decreased protein expression of deubiquitinating enzymes isopeptidase T and ubiquitin-fusion degradation system (38) have been observed. Expression of E3s murine double minute 2 (9) and atrogin-1 (25) is also increased in heart failure, and MuRF1 protein expression is increased following mechanical unloading with LVAD (98). The overall observed increase in expression of ubiquitination machinery in failing hearts may be in response to an increased protein burden, from increased protein synthesis that accompanies the hypertrophic response or an excess of damaged or modified proteins to be targeted for proteasomal degradation.…”

Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro

“…The major protein degradation pathway involves UPS, which is ubiquitous throughout the body, and degrades ubiquitinconjugated proteins via the 26S proteasome [8,9] . A number of studies have shown that E3 ubiquitin ligase MuRF1 catalyzes the ubiquitylation and breakdown of cardiac structural proteins and plays a pivotal role in cardiac atrophy [29] . It has also recently been reported that myocardium lacking MuRF1 expression has exaggerated cardiac hypertrophy in response to prohypertrophic stimulation [13] .…”