Cardiac Muscle Ring Finger-1—Friend or Foe?

Willis, Monte S.; Zungu, Makhosazane; Patterson, Cam

doi:10.1016/j.tcm.2010.03.001

Cited by 9 publications

(9 citation statements)

References 27 publications

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“…However, to our knowledge, this concept had yet to be translated to an in vivo setting, such as animal models that mimic clinically relevant disease conditions. It is likely that a complete inhibition of MuRF1, such as blockade of its ring finger functions or by gene inactivation, may be detrimental as MuRF1 is suggested to have additional functions beyond simply that of an atrogin 28. For example, MuRF1 knockout (KO) mice are much more susceptible to cardiac hypertrophy,28 and patients with null mutations in the MuRF1 gene also suffer a similar fate,29 which indicates that basal MuRF1 expression is required for myocyte homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…It is likely that a complete inhibition of MuRF1, such as blockade of its ring finger functions or by gene inactivation, may be detrimental as MuRF1 is suggested to have additional functions beyond simply that of an atrogin 28. For example, MuRF1 knockout (KO) mice are much more susceptible to cardiac hypertrophy,28 and patients with null mutations in the MuRF1 gene also suffer a similar fate,29 which indicates that basal MuRF1 expression is required for myocyte homeostasis. In addition, small molecules directed to the ubiquitin transfer catalysing ring finger of MuRF1 might provide toxicity by lack of target specificity and thus leading to protein aggregates 18, 27, 30.…”

Section: Discussionmentioning

confidence: 99%

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Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

Bowen¹,

Adams²,

Werner

et al. 2017

J cachexia sarcopenia muscle

119

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BackgroundMuscle ring finger 1 (MuRF1) is a muscle‐specific ubiquitin E3 ligase activated during clinical conditions associated with skeletal muscle wasting. Yet, there remains a paucity of therapeutic interventions that directly inhibit MuRF1 function, particularly in vivo. The current study, therefore, developed a novel compound targeting the central coiled coil domain of MuRF1 to inhibit muscle wasting in cardiac cachexia.MethodsWe identified small molecules that interfere with the MuRF1–titin interaction from a 130 000 compound screen based on Alpha Technology. A subset of nine prioritized compounds were synthesized and administrated during conditions of muscle wasting, that is, to C2C12 muscle cells treated with dexamethasone and to mice treated with monocrotaline to induce cardiac cachexia.ResultsThe nine selected compounds inhibited MuRF1–titin complexation with IC50 values <25 μM, of which three were found to also inhibit MuRF1 E3 ligase activity, with one further showing low toxicity on cultured myotubes. This last compound, EMBL chemical core ID#704946, also prevented atrophy in myotubes induced by dexamethasone and attenuated fibre atrophy and contractile dysfunction in mice during cardiac cachexia. Proteomic and western blot analyses showed that stress pathways were attenuated by ID#704946 treatment, including down‐regulation of MuRF1 and normalization of proteins associated with apoptosis (BAX) and protein synthesis (elF2B‐delta). Furthermore, actin ubiquitinylation and proteasome activity was attenuated.ConclusionsWe identified a novel compound directed to MuRF1's central myofibrillar protein recognition domain. This compound attenuated in vivo muscle wasting and contractile dysfunction in cardiac cachexia by protecting de novo protein synthesis and by down‐regulating apoptosis and ubiquitin‐proteasome‐dependent proteolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

Bowen¹,

Adams²,

Werner

et al. 2017

J cachexia sarcopenia muscle

119

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“…Using an unbiased approach, we found many dysregulated genes, which participate in metabolic pathways. A link between murf‐1, protein degradation, the basis of muscle atrophy, and metabolic changes has been described for metabolic pathways …”

Section: Discussionmentioning

confidence: 99%

Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction

Veltkamp

Uhlmann

Marinescu

et al. 2018

J cachexia sarcopenia muscle

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Background Stroke can lead to cardiac dysfunction in patients, but the mechanisms underlying the interaction between the injured brain and the heart are poorly understood. The objective of the study is to investigate the effects of experimental murine stroke on cardiac function and molecular signalling in the heart. Methods and results Mice were subjected to filament‐induced left middle cerebral artery occlusion for 30 or 60 min or sham surgery and underwent repetitive micro‐echocardiography. Left ventricular contractility was reduced early (24–72 h) but not late (2 months) after brain ischaemia. Cardiac dysfunction was accompanied by a release of high‐sensitive cardiac troponin (hsTNT (ng/ml): d1: 7.0 ± 1.0 vs. 25.0 ± 3.2*; d3: 7.3 ± 1.1 vs. 52.2 ± 16.7*; d14: 5.7 ± 0.8 vs. 5.2 ± 0.3; sham vs. 60 min. MCAO; mean ± SEM; * p < 0.05); reduced heart weight (heart weight/tibia length ratio: d1: 6.9 ± 0.2 vs. 6.4 ± 0.1*; d3: 6.7 ± 0.2 vs. 5.8 ± 0.1*; d14: 6.7 ± 0.2 vs. 6.4 ± 03; sham vs. 60 min. MCAO; mean ± SEM; * p < 0.05); resulting from cardiomyocyte atrophy (cardiomyocyte size: d1: 12.8% ± 0.002**; d3: 13.5% ± 0.002**; 14d: 6.3% ± 0.003*; 60 min. MCAO vs. sham; mean ± SEM; ** p < 0.01; * p < 0.05), accompanied by increased atrogin‐1 and the E3 ubiquitin ligase murf‐1. Net norepinephrine but not synthesis was increased, suggesting a reduced norepinephrine release or an increase of norepinephrine re‐uptake, resulting in a functional denervation. Transcriptome analysis in cardiac tissue identified the transcription factor peroxisome proliferator‐activated receptor gamma as a potential mediator of stroke‐induced transcriptional dysregulation involved in cardiac atrophy. Conclusions Stroke induces a complex molecular response in the heart muscle with immediate but transient cardiac atrophy and dysfunction.

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“…Muscle-specific RING finger protein 1 (MuRF1, Trim63) is a striated muscle-specific ubiquitin ligase involved in protein quality control of the muscle sarcomere by targeting numerous proteins for polyubiquitin-dependent proteasomal degradation, including troponin I, muscle actin, β/slow myosin heavy chain and myosin binding protein-C (7–10). Ubiquitin ligases, including MuRF family proteins, function as distinct molecular regulators by which the heart controls not only sarcomeric structure, but also cellular signaling pathways implicated in multiple models of cardiac disease, both in maladaptive and cardioprotective roles (5,9,11–16). Targeting ubiquitin ligases in the heart may allow for more precise, single therapy manipulation of a smaller, specific subset of substrate proteins that contribute to disease-causing mechanisms while avoiding the negative cardiovascular effects observed with global proteasome inhibition (17,18).…”

Section: Introductionmentioning

confidence: 99%

Diggin′ on U(biquitin): A Novel Method for the Identification of Physiological E3 Ubiquitin Ligase Substrates

Rubel

Schisler

Hamlett

et al. 2013

Cell Biochem Biophys

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The ubiquitin-proteasome system (UPS) plays a central role in maintaining protein homeostasis, emphasized by a myriad of diseases that are associated with altered UPS function such as cancer, muscle-wasting, and neurodegeneration. Protein ubiquitination plays a central role in both the promotion of proteasomal degradation as well as cellular signaling through regulation of the stability of transcription factors and other signaling molecules. Substrate specificity is a critical regulatory step of ubiquitination and is mediated by ubiquitin ligases. Recent studies implicate ubiquitin ligases in multiple models of cardiac diseases such as cardiac hypertrophy, atrophy, and ischemia/reperfusion injury, both in a cardioprotective and maladaptive role. Therefore, identifying physiological substrates of cardiac ubiquitin ligases provides both mechanistic insights into heart disease as well as possible therapeutic targets. Current methods identifying substrates for ubiquitin ligases rely heavily upon non-physiologic in vitro methods, impeding the unbiased discovery of physiological substrates in relevant model systems. Here we describe a novel method for identifying ubiquitin ligase substrates utilizing Tandem Ubiquitin Binding Entities (TUBE) technology, two-dimensional differential in gel electrophoresis (2-D DIGE), and mass spectrometry, validated by the identification of both known and novel physiological substrates of the ubiquitin ligase MuRF1 in primary cardiomyocytes. This method can be applied to any ubiquitin ligase, both in normal and disease model systems, in order to identify relevant physiological substrates under various biological conditions, opening the door to a clearer mechanistic understanding of ubiquitin ligase function and broadening their potential as therapeutic targets.

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Cardiac Muscle Ring Finger-1—Friend or Foe?

Cited by 9 publications

References 27 publications

Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction

Diggin′ on U(biquitin): A Novel Method for the Identification of Physiological E3 Ubiquitin Ligase Substrates

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