New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations

Olivé, Montse; Abdul-Hussein, Saba; Oldfors, Anders; González-Costello, José; Ven, P.F.M. van der; Fürst, Dieter O.; González, Laura; Moreno, Dolores; Torrejón‐Escribano, Benjamín; Alió, Josefina; Pou, Adolf; Ferrer, Isidro; Tajsharghi, Homa

doi:10.1093/hmg/ddv311

Cited by 23 publications

(33 citation statements)

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“…Of note, recently combined homozygous MuRF1 and heterozygous MuRF3 mutations were shown to cause a protein aggregate myopathy and cardiomyopathy in patients, which was reminiscent of the MuRF1 and MuRF3 DKO phenotype described by us . Importantly, after comprehensive screening for mutations in several sarcomeric genes, our description of the MuRF1 and MuRF3 DKO mouse phenotype prompted the authors to search for mutations in the MuRF1 and MuRF3 genes . This analysis by Olive et al .…”

Section: Discussionmentioning

confidence: 88%

“…This analysis by Olive et al . now led to a new disease entity of skeletal muscle and cardiac protein aggregate myopathy . However, if combined MuRF2 and MuRF3 mutations occur in patients and are causative for protein aggregate myopathy and cardiomyopathy needs to be verified.…”

Section: Discussionmentioning

confidence: 99%

“…4 Importantly, after comprehensive screening for mutations in several sarcomeric genes, our description of the MuRF1 and MuRF3 DKO mouse phenotype prompted the authors to search for mutations in the MuRF1 and MuRF3 genes. 30 This analysis by Olive et al now led to a new disease entity of skeletal muscle and cardiac protein aggregate myopathy. 30 However, if combined MuRF2 and MuRF3 mutations occur in patients and are causative for protein aggregate myopathy and cardiomyopathy needs to be verified.…”

Section: Discussionmentioning

confidence: 99%

“…30 This analysis by Olive et al now led to a new disease entity of skeletal muscle and cardiac protein aggregate myopathy. 30 However, if combined MuRF2 and MuRF3 mutations occur in patients and are causative for protein aggregate myopathy and cardiomyopathy needs to be verified. Nevertheless, in those patients suffering from protein aggregate myopathies in whom mutations in sarcomeric genes were excluded, it appears to be reasonable to search for mutations in MuRF1, MuRF2 and MuRF3.…”

Section: Discussionmentioning

confidence: 99%

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Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

Lodka

Pahuja

Geers-Knörr

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundThe Muscle‐specific RING‐finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with noticeable functional redundancy. However, if this redundancy is important for muscle function in vivo is unknown. Our objective was to investigate cooperative function of MuRF2 and MuRF3 in the skeletal muscle and the heart in vivo.Methods MuRF2 and MuRF3 double knockout mice (DKO) were generated and phenotypically characterized. Skeletal muscle and the heart were investigated by morphological measurements, histological analyses, electron microscopy, immunoblotting, and real‐time PCR. Isolated muscles were subjected to in vitro force measurements. Cardiac function was determined by echocardiography and working heart preparations. Function of cardiomyocytes was measured in vitro. Cell culture experiments and mass‐spectrometry were used for mechanistic analyses.ResultsDKO mice showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO soleus and extensor digitorum longus. Additionally, a fibre type shift towards slow/type I fibres occurred in DKO soleus and extensor digitorum longus. MuRF2 and MuRF3‐deficient hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the myosin heavy chain isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in DKO hearts.ConclusionsThe redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

Lodka

Pahuja

Geers-Knörr

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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“…In two other cases, CTNNA3 and SUCLA2, the identified TiP interaction partners TRIM54 and ARL6IP1, respectively, themselves cause similar diseases with overlapping symptoms 73,74 , reinforcing the likely pathogenic relevance of the interactions. Overall, this study yields hypotheses of molecular mechanisms for otherwise unexplained tissue-specific phenotypes of seven Mendelian diseases ( Fig.…”

Section: Molecular Mechanisms Of Tissue-specific Mendelian Diseasesmentioning

confidence: 85%

A reference map of the human protein interactome

Luck

Kim

Lambourne

et al. 2019

Preprint

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Global insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence revolutionized human genetics, a reference map of the human interactome network is critical to fully understand genotype-phenotype relationships. Here we present the first human "all-by-all" binary reference interactome map, or "HuRI". With ~53,000 highquality protein-protein interactions (PPIs), HuRI is approximately four times larger than the information curated from small-scale studies available in the literature. Integrating HuRI with genome, transcriptome and proteome data enables the study of cellular function within essentially any physiological or pathological cellular context. We demonstrate the use of HuRI in identifying specific subcellular roles of PPIs and protein function modulation via splicing during brain development. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms underlying tissue-specific phenotypes of Mendelian diseases. HuRI thus represents an unprecedented, systematic reference linking genomic variation to phenotypic outcomes.

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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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New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations

Cited by 23 publications

References 0 publications

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

Muscle RING-finger 2 and 3 maintain striated-muscle structure and function

A reference map of the human protein interactome

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

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