MuRF1 activity is present in cardiac mitochondria and regulates reactive oxygen species production in vivo

Mattox, Taylor A.; Young, Martin E.; Rubel, Carrie E.; Spaniel, Carolyn; Rodriguez, Jessica; Grevengoed, Trisha J.; Gautel, Mathias; Xu, Zhelong; Anderson, Ethan J.; Willis, Monte S.

doi:10.1007/s10863-014-9549-9

Cited by 23 publications

(14 citation statements)

References 53 publications

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“…MuRF1 has recently been reported to interact with multiple proteins found in mitochondria [26], with increased cardiac MuRF1 expression affecting mitochondrial ROS production in vivo [27]. Because fenofibrate can affect cardiac mitochondrial respiration [28–30], we next investigated mitochondria number and ultrastructure in MuRF1−/− hearts after fenofibrate treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Parry

Desai

Schisler

et al. 2016

Cardiovascular Pathology

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The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1−/− mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1 +/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1−/− mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1−/− genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <−4 log fold change; P≤.0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis.

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Section: Resultsmentioning

confidence: 99%

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Parry

Desai

Schisler

et al. 2016

Cardiovascular Pathology

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“…MURF1 levels are increased with ROS (Doyle et al, 2011; Li et al, 2003), but MURF1 also has a role in regulating mitochondrial induced ROS production (Mattox et al, 2014). As ROS is increased during HS and reloading, we examined whether antioxidant protein levels that are associated primarily with the mitochondria (MnSOD) or cytosol (CuZnSOD) regions of the muscle would change along with MURF1 protein levels.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

Takahashi

Suzuki

Mohamed

et al. 2017

Experimental Gerontology

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We have previously found that Epigallocatechin-3-gallate (EGCg), an abundant catechin in green tea, reduced apoptotic signaling and improved muscle recovery in response to reloading after hindlimb suspension (HS). In this study, we investigated if EGCg altered autophagy signaling in skeletal muscle of old rats in response to HS or reloading after HS. Fischer 344 x Brown Norway inbred rats (age 34 mo.) were given 1 ml/day of purified EGCg (50 mg/kg body weight), or the same sample volume of the vehicle by gavage. One group of animals received HS for 14 days and the second group of rats received 14 days of HS, then the HS was removed and they were allowed to recover by ambulating normally around the cage for two weeks. EGCg decreased a small number of autophagy genes in control muscles, but it increased the expression of other autophagy genes (e.g., ATG16L2, SNCA, TM9SF1, Pink1, PIM-2) and HS did not attenuate these increases. HS increased Beclin1, ATG7 and LC3-II/I protein abundance in hindlimb muscles. Relative to vehicle treatment, EGCg treatment had greater ATG12 protein abundance (35.8%, P<0.05), but decreased Beclin1 protein levels (−101.1%, P<0.05) after HS. However, in reloaded muscles, EGCg suppressed Beclin1 and LC3-II/I protein abundance as compared to vehicle treated muscles. EGCg appeared to “prime” autophagy signaling before and enhance autophagy gene expression and protein levels during unloading in muscles of aged rats, perhaps to improve the clearance of damaged organelles. However, EGCg suppressed autophagy signaling after reloading, potentially to increase the recovery of hindlimb muscles mass and function after loading is restored.

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“…Mitochondrial ROS may be a cytoprotective strategy against oxidative stress associated with disease processes such as aging (48), diabetes (49, 50) or ischemia reperfusion injury (51–54). In the current study, although mitochondrial oxidative burden (as assessed by mitosox) was reduced in SD cells, several antioxidant genes including FoxO1 and its downstream targets MnSOD, Hmox-1 and catalase were up-regulated.…”

Section: Discussionmentioning

confidence: 99%

The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress

Sengupta

Guang

O‘Donnell

et al. 2016

Free Radical Biology and Medicine

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Diurnal oscillations in the expression of antioxidant genes imply that protection against oxidative stress is circadian-gated. We hypothesized that stabilization of the core circadian gene Rev-erbα (Nr1d1) improves cellular bioenergetics and protects against nutrient deprivation and oxidative stress. Compared to WT, mouse lung fibroblasts (MLG) stably transfected with a degradation resistant Rev-erbα (Ser55/59 to Asp; hence referred to as SD) had 40% higher protein content, 1.5-fold higher mitochondrial area (confocal microscopy), doubled oxidative phosphorylation by high-resolution respirometry (Oroboros) and were resistant to glucose deprivation for 24h. This resulted from a 4-fold reduction in mitophagy (L3CB co-localized with MitoTracker Red) vs WT. Although PGC1α protein expression was comparable between SD and WT MLG cells, the role of mitochondrial biogenesis in explaining increased mitochondrial mass in SD cells was less clear. Embryonic fibroblasts (MEF) from C57Bl/6-SD transgenic mice, had a 9-fold induction of FoxO1 mRNA and increased mRNA of downstream antioxidant targets heme oxygenase-1 (HO-1), Mn superoxide dismutase and catalase (1.5, 2 fold and 2 fold respectively) vs WT. This allowed the SD cells to survive 1h incubation with 500 μM H2O2 as well as 24hrs of exposure to 95% O2 and remain attached whereas most WT cells did not. These observations establish a mechanistic link between the metabolic functions of Rev-erbα with mitochondrial homeostasis and protection against oxidative stress.

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MuRF1 activity is present in cardiac mitochondria and regulates reactive oxygen species production in vivo

Cited by 23 publications

References 53 publications

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress

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