Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 121, Issue -, Pages 287-296Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2018.07.248
Keywords
Hypertrophic cardiomyopathy; MLP C58G mutation; Mouse knock-in model; In vivo phenotyping; RNAseq transcriptome analysis; Protein depletion; Proteasome; Sarcomere
Categories
Funding
- British Heart Foundation (BHF) [FS/12/40/29712]
- BHF Centre of Research Excellence, Oxford [RE/13/1/30181]
- Clarendon Fund doctoral scholarship
- BHF Centre of Research Excellence, King's College London [RE/13/2/30182]
- BHF
- European Commission [LSHM-CT- 2007-037273, HEALTH-F2-2013-601456, 734791, 751739]
- Wellcome Trust [201543/B/16/Z]
- TriPartite Immunometabolism Consortium [TrIC]- Novo Nordisk Foundation [NNF15CC0018486]
- National Institute of Health Research
- BBSRC [BB/R001049/1, BB/M007103/1, BB/P001599/1]
- BBSRC [BB/M007103/1, BB/R001049/1, BB/P001599/1] Funding Source: UKRI
- MRC [G0400153] Funding Source: UKRI
- Wellcome Trust [201543/B/16/Z] Funding Source: Wellcome Trust
- Marie Curie Actions (MSCA) [734791, 751739] Funding Source: Marie Curie Actions (MSCA)
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Cysteine and glycine rich protein 3 (CSRP3) encodes Muscle LIM Protein (MLP), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes. To gain insight into the disease mechanisms involved, we generated a knock-in mouse (KI) model, carrying the well documented HCM-causing CSRP3 mutation C58G. In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements. Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts. Further ex vivo analyses validated the activation of these pathways at transcript and protein level. Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action. Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins. In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations.
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