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Status |
Public on Apr 01, 2013 |
Title |
Muscle Ring Finger 1 (MuRF1) and MuRF2 are Necessary but Functionally Redundant During Developmental Cardiac Growth and Regulate E2F1-Mediated Gene Expression In Vivo |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
Muscle ring finger (MuRF) proteins have been implicated in the transmission of mechanical forces to nuclear cell signaling pathways through their association with the sarcomere. We recently reported that MuRF1, but not MuRF2, regulated pathologic cardiac hypertrophy in vivo. This was surprising since MuRF1 and MuRF2 interact redundantly with sarcomeric proteins in yeast two hybrid studies, and form both homo- and hetero-dimers with each other. To determine if MuRF1 and MuRF2 were functionally redundant during development, we created mice lacking either 3 or 4 of the MuRF1 and MuRF2 alleles and compared them functionally. Surprisingly, only mice missing all four MuRF1 and MuRF2 alleles (MuRF1-/-//MuRF2-/-) developed a spontaneous hypertrophic cardiomyopathy - mice that were null for one of the genes, but heterozygous for the other (i.e. MuRF1-/-//MuRF2+/- or MuRF1+/-//MuRF2-/-) were phenotypically identical to wild type mice. Electron microscopy of the hearts of MuRF1-/-//MuRF2-/-(MuRF1/MuRF2 DN) mice identified altered Z disc and M line architecture, and a distinct swelling of mitochondria. MuRF1-/-//MuRF2-/- mouse hearts displayed increased expression of genes associated with fetal cardiac metabolism, including smooth muscle actin and b myosin heavy chain, suggesting that the cardiac hypertrophy seen in these mice was associated with a reversion to a fetal gene program. Despite our prediction that we would also see an increase in glucose compared to fatty acid oxidation (another trait of fetal cardiac metabolism) we saw that MuRF1-/-//MuRF2-/- heart homogenates oxidized significantly less glucose compared to controls, suggesting an important role for MuRF1 and MuRF2 in the regulation of glucose metabolism in vivo. This study identifies a previously unreported redundancy in the function of MuRF proteins in normal cardiac development.
Keywords: Genetic modification.
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Overall design |
Four strain-matched groups of 12 week old mice were investigated: 1) MuRF1 -/- MuRF2 -/-; 2) MuRF1 +/+ MuRF2 +/+; 3) MuRF1 -/- MuRF2 +/-; 4) MuRF1 +/- MuRF2 -/-. Biological replicates: 4 WT, 4 MuRF1 -/- // MuRF2 -/-, 4 MuRF1 +/- //MuRF2 -/-, 4 MuRF1 -/- // MuRF2 +/-. Hearts harvested. One replicate per array.
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Contributor(s) |
Willis MS, Wadosky KM, Rodriguez J, Schisler JC, Lockyer P, Hilliard EG, Glass DJ, Patterson C |
Citation(s) |
23512667 |
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Submission date |
Jan 22, 2009 |
Last update date |
Jan 12, 2017 |
Contact name |
Monte Shaw Willis |
E-mail(s) |
monte_willis@med.unc.edu
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Phone |
919-843-1938
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Organization name |
University of North Carolina
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Department |
Pathology & Laboratory Medicine
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Street address |
103 Mason Farm Road, MBRB 2340B
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City |
Chapel Hill |
State/province |
NC |
ZIP/Postal code |
27599-7525 |
Country |
USA |
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Platforms (1) |
GPL7202 |
Agilent-014868 Whole Mouse Genome Microarray 4x44K G4122F (Probe Name version) |
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Samples (16)
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GSM362602 |
MuRF1 -/- // MuRF2 -/-: Biological replicate 1. |
GSM362603 |
MuRF1 -/- // MuRF2 -/-: Biological replicate 2. |
GSM362604 |
MuRF1 +/+ // MuRF2 +/+: Biological replicate 1. |
GSM362605 |
MuRF1 +/+ // MuRF2 +/+: Biological replicate 2. |
GSM362606 |
MuRF1 -/- // MuRF2 +/-: Biological replicate 1. |
GSM362607 |
MuRF1 -/- // MuRF2 +/-: Biological replicate 2. |
GSM362608 |
MuRF1 -/- // MuRF2 +/-: Biological replicate 3. |
GSM362609 |
MuRF1 -/- // MuRF2 +/-: Biological replicate 4. |
GSM362610 |
MuRF1 +/+ // MuRF2 +/+: Biological replicate 3. |
GSM362611 |
MuRF1 -/- // MuRF2 -/-: Biological replicate 3. |
GSM362612 |
MuRF1 -/- // MuRF2 -/-: Biological replicate 4. |
GSM362613 |
MuRF1 +/+ // MuRF2 +/+: Biological replicate 4. |
GSM362614 |
MuRF1 +/- // MuRF2 -/-: Biological replicate 1. |
GSM362615 |
MuRF1 +/- // MuRF2 -/-: Biological replicate 2. |
GSM362616 |
MuRF1 +/- // MuRF2 -/-: Biological replicate 3. |
GSM362617 |
MuRF1 +/- // MuRF2 -/-: Biological replicate 4. |
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Relations |
BioProject |
PRJNA111657 |