Cardiomyocyte-specific miRNA-30c over-expression causes dilated cardiomyopathy.
MicroRNAs (miRNAs) regulate many aspects of cellular function and their deregulation has been implicated in heart disease. MiRNA-30c is differentially expressed in the heart during the progression towards heart failure and in vitro studies hint to its importance in cellular physiology. As little is known about the in vivo function of miRNA-30c in the heart, we generated transgenic mice that specifically overexpress miRNA-30c in cardiomyocytes. We show that these mice display no abnormalities until about 6 weeks of age, but subsequently develop a severely dilated cardiomyopathy. Gene expression analysis of the miRNA-30c transgenic hearts before onset of the phenotype indicated disturbed mitochondrial function. This was further evident by the downregulation of mitochondrial oxidative phosphorylation (OXPHOS) complexes III and IV at the protein level. Taken together these data indicate impaired mitochondrial function due to OXPHOS protein depletion as a potential cause for the observed dilated cardiomyopathic phenotype in miRNA-30c transgenic mice. We thus establish an in vivo role for miRNA-30c in cardiac physiology, particularly in mitochondrial function.
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands; Interuniversitair Cardiologisch Instituut Nederland (ICIN-NHI), Utrecht, The Netherlands.
Wino J
WJ
Wijnen
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Ingeborg
I
van der Made
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Stephanie
S
van den Oever
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Monika
M
Hiller
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Bouke A
BA
de Boer
Department of Cell Biology and Histology, Leeuwenhoek Center of Advanced Microscopy (LCAM), Academic Medical Center, Amsterdam, The Netherlands.
Daisy I
DI
Picavet
Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
Iliana A
IA
Chatzispyrou
Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
Riekelt H
RH
Houtkooper
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Anke J
AJ
Tijsen
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Jaco
J
Hagoort
Department of Cell Biology and Histology, Leeuwenhoek Center of Advanced Microscopy (LCAM), Academic Medical Center, Amsterdam, The Netherlands.
Henk
H
van Veen
Department of Cell Biology and Histology, Leeuwenhoek Center of Advanced Microscopy (LCAM), Academic Medical Center, Amsterdam, The Netherlands.
Vincent
V
Everts
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Jan M
JM
Ruijter
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Yigal M
YM
Pinto
Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Esther E
EE
Creemers
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004452:Echocardiography; D020869:Gene Expression Profiling; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins