Muscle RING-Finger Protein-1 (MuRF1) as a Connector of Muscle Energy Metabolism and Protein Synthesis

Koyama, Suguru; Hata, Shoji; Witt, Christian; Ono, Yasuko; Lerche, Stefanie; Ojima, Koichi; Chiba, Tomoki; Doi, Naoko; Kitamura, Fujiko; Tanaka, Keiji; Abe, Keiko; Witt, Stephanie H.; Rybin, Vladimir; Gasch, Alexander; Franz, Thomas; Labeit, Siegfried; Sorimachi, Hiroyuki

doi:10.1016/j.jmb.2007.11.049

Cited by 141 publications

(126 citation statements)

References 56 publications

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“…The eIF2B pathway is a known translational regulator of protein synthesis, with evidence showing that its content can directly influence fibre size 31. The direct targeting of elF2B by MuRF1 appears plausible because our previous yeast two‐hybrid screens identified elF2B as a MuRF1 interacting factor, linking MuRF1 as a negative regulator of protein synthesis 32. In line with a direct regulation of protein translation by MuRF1, injection of D5‐phenylalanine into MuRF1 KO mice demonstrated an elevated muscle protein translation,27 while MuRF1 KO mice are protected against a reduction in protein synthesis following DEX treatment 11.…”

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

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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%

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

Bowen¹,

Adams²,

Werner

et al. 2017

J cachexia sarcopenia muscle

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119

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“…Evidence suggests that MyoD and M-CK can be degraded by MAFbx and MuRF1, respectively, through the ubiquitin-proteasome system [8,10,12]. We therefore investigated changes in MyoD and M-CK expression in the skeletal muscles of chicks subjected to fasting and refeeding, using Western blotting.…”

Section: Downregulation Of Myod and M-ck In Fasted Skeletal Muscle Timentioning

confidence: 99%

“…Muscle creatine kinase (M-CK) is a crucial enzyme in energy metabolism and catalyzes the reversible conversion of MgATP and creatine to MgADP and phosphocreatine [11]. Previous studies have demonstrated that MAFbx and MuRF1 degrade MyoD and M-CK, respectively, in skeletal muscle [10,12].…”

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confidence: 99%

Effects of fasting and refeeding on expression of MAFbx and MuRF1 in chick skeletal muscle

et al. 2011

Sci. China Life Sci.

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The present study investigated the effects of fasting and refeeding on the expression of proteasome-related genes and their downstream targets in the skeletal muscles of chicks. Seven-day-old chicks were fasted for 24 or 48 h and then refed for 4 h. The expression levels of MAFbx and MuRF1, which function as E3 ligases in the ubiquitin-proteasome system, were investigated at the mRNA and protein levels. MAFbx and MuRF1 expression were increased by fasting and these increases were downregulated by refeeding. The expression of the target proteins of these E3 ligases, MyoD and M-CK, was also analyzed. The levels of these proteins were downregulated by fasting, and these decreases were rescued by refeeding. The results of this study indicate that fasting stimulates MAFbx and MuRF1 expression in chicks, possibly leading to increased degradation of their corresponding target proteins.

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“…In neural cells, HIBADH may use valine imported into the brain for the generation of energy. In previous study, muscle RINGFinger protein-1 (MuRF1), which has been proposed to trigger muscle protein degradation during pathophysiological muscle wastage, interacted with HIBADH to regulate the amino acid metabolism [36].…”

Section: Introductionmentioning

confidence: 99%

Characterization of 3-hydroxyisobutyrate dehydrogenase, HIBADH, as a sperm-motility marker

Tasi

Chao

Chung

et al. 2013

J Assist Reprod Genet

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Purpose Asthenozoospermia is a major cause of male infertility. However, the molecular mechanisms underlying spermmotility defects remain largely unknown in the majority of cases. In our previous study, we applied a proteomic approach to identify unknown proteins that were downregulated in spermatozoa with low motility compared to spermatozoa with good motility. Several sperm motility-related proteins have been identified. In this study, 3-hydroxyisobutyrate dehydrogenase (HIBADH), one of the proteins identified using the proteomic tools, is further characterized.Methods Reverse-transcription polymerase chain reactions (RT-PCR), western blotting, and immunofluorescence assays (IFA) were preformed to investigate the expression pattern. The enzymatic activity of HIBADH was evaluated in sperm with good (>50 %), moderate (< 50 %) and lower motility (< 20 %). Results Using RT-PCR, we found that transcripts of HIBADH are enriched in the cerebellum, heart, skeletal muscle, uterus, placenta, and testes of male humans. In western blotting, it is expressed in the placenta, testes, and spermatozoa. During spermiogenesis, HIBADH is located at Capsule HIBADH is involved in the mitochondrial function of spermatozoa and maintains sperm motility. It may serve as a spermmotility marker.Pao-Lin Kuo and Ying-Hung Lin contributed equally to co-corresponding author. Assist Reprod Genet (2013) 30:505-512 DOI 10.1007 the mid-piece (a specialized development from the mitochondria) of elongating, elongated, and mature sperm. The enzymatic activity of HIBADH in sperm with moderate and lower motility were significantly reduced compared with good motility (P<0.0001 and P<0.05, respectively). Conclusions Our study indicated that HIBADH is involved in the mitochondrial function of spermatozoa, and maintains sperm motility. It may serve as a sperm-motility marker. Electronic supplementary material

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Muscle RING-Finger Protein-1 (MuRF1) as a Connector of Muscle Energy Metabolism and Protein Synthesis

Cited by 141 publications

References 56 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

Effects of fasting and refeeding on expression of MAFbx and MuRF1 in chick skeletal muscle

Characterization of 3-hydroxyisobutyrate dehydrogenase, HIBADH, as a sperm-motility marker

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