Cardiac Muscle Ring Finger-1 Increases Susceptibility to Heart Failure In Vivo

Abstract

Abstract-Muscle ring finger (MuRF)1 is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates and heterodimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal, whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy, indicating cooperative control of muscle mass by MuRF1 and MuRF2. To identify the unique role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg ϩ ) hearts exhibited a nonprogressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by transaortic constriction (TAC) induced rapid failure of MuRF1 Tg ϩ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg ϩ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg ϩ mice did not differ from wild-type mice despite the depressed contractility following TAC. In comparing the level and activity of creatine kinase (CK) between wild-type and MuRF1 Tg ϩ hearts, we found that mCK and CK-M/B protein levels were unaffected in MuRF1 Tg ϩ hearts; however, total CK activity was significantly inhibited. We conclude that increased expression of cardiac MuRF1 results in a broad disruption of primary metabolic functions, including alterations in CK activity that leads to increased susceptibility to heart failure following TAC. This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo. Key Words: muscle ring finger-1 Ⅲ MuRF1 Ⅲ ubiquitin ligase Ⅲ cardiac hypertrophy Ⅲ heart failure Ⅲ creatine kinase T he muscle ring finger (MuRF) proteins are striated muscle-specific proteins that have been implicated in various aspects of contractile regulation and myogenic responses. 1 MuRF1 is a well-characterized RING finger-dependent ubiquitin ligase that targets sarcomere proteins, such as cardiac troponin (cTn)I, during the process of skeletal muscle atrophy. 2,3 MuRF1 has also been implicated in the regulation of cardiac myocyte size and contractility [3][4][5] and inhibits the development of cardiac hypertrophy, 6,7 a dynamic process commonly thought of as a precursor to heart failure. 8 To date, the study of the regulation of cardiac muscle mass by MuRF1 has centered around its involvement in the regulation of sarcomere protein degradation. Although this is certainly an important function, in this report, we propose that MuRF1 operates in a broader capacity that encompasses both protein turnover as well as control of cardiac metabolism.Soon after the discovery of MuRF1, the related proteins MuRF2 and MuRF3 were identified as interacting proteins capable of forming hetero...

Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling

“…Densitometry analysis was performed using Quantity One 1-D Analysis Software (Bio-Rad, Hercules, CA Animals. MuRF1 Ϫ/Ϫ mice (129S/C57BL6) and ␣-MHC-MuRF1 (cardiac-specific) transgenic mice (DBA/C57BL6) aged 8 -16 wk were used as described (53,56). After 5 wk of monitored wheel running exercise (or sham exercise), mice were euthanized and hearts flash-frozen and stored at Ϫ80°C or perfusion fixed in 4% paraformaldehyde.…”

“…Female mice were assigned to either unloaded (no resistance) wheel running or sedentary control groups, as described previously (54). Mice were randomly assigned to running or sham control groups and monitored in parallel by echocardiography on conscious mice using a Visual Sonics Vevo 770 and 2100 ultrasound biomicroscopy system at baseline, 2 wk, and 5 wk, as described previously (55,56).…”

Role of the Ubiquitin Proteasome System in the Heart

“…92 Finally, using a gain-of-function approach in mice, it was demonstrated that MuRF1 overexpression induces a broad array of metabolic abnormalities, leading to increased susceptibility to heart failure after TAC. 93 Interestingly, it appears that the inhibitory effect of MuRF1 on myocardial hypertrophy depends on the stimulus, as MuRF1 only prevented maladaptive pathological hypertrophy in vivo but not adaptive physiological hypertrophy.…”

“…92 MuRF1 activity is also upregulated in failing hearts, and high levels of MuRF1 in mouse hearts increase the likelihood of heart failure. 93 Low levels of MuRF1 and Atrogin/MAFbox remote from the site of infarction are speculated to permit hypertrophy in these areas. 94 MuRF1 not only activates antihypertrophic pathways within the myocardium, it also mediates cardiac atrophy in vivo.…”

Insulin-like growth factor-1 restores dexamethasone-induced heart growth arrest in rats: the role of the ubiquitin pathway

“…Studies showing that the E3-ligases are critical for maintenance of heart mass further support the concept that the Ub pathway plays an important role in heart physiology. [10][11][12] The Ub pathway has also been implicated in various conditions affecting the heart such as diabetes, dilated cardiomyopathy, oxidative stress, and ischemia-reperfusion injury. 8,[13][14][15] Animal studies suggest that cardiac muscle is more resistant to the catabolic effects of glucocorticoids compared to skeletal muscle.…”