Skip to main content

Advertisement

SpringerLink
Log in

Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA

  • Mitochondria at the heart of cardioprotection
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

All the necessary data has been provided within the manuscript. Any further data are available from the corresponding author upon request.

Abbreviations

RBP:

RNA-binding protein

AAV:

Adeno-associated virus

GFP:

Green fluorescent protein

UTR:

Untranslated region

DNA:

Deoxyribonucleic acid

RNA:

Ribonucleic acid

rRNA:

Ribosomal RNA

tRNA:

Transfer RNA

mRNA:

Messenger RNA

NCBI:

National center for biotechnology information

PCR:

Polymerase chain reaction

DAPI:

4′,6-Diamidino-2-phenylindole

TEM:

Transmission electron microscope

RRM:

RNA recognition motifs

LC–MS/MS:

Liquid chromatography with tandem mass spectrometry

GO:

Gene ontology

TCA:

Tricarboxylic acid

ARE:

Adenylate-uridylate-rich elements

TMRE:

Tetramethylrhodamine, ethyl ester

TAC:

Trans-aortic constriction

FPKM:

Fragment per kilobase of transcript per million read pairs

MOI:

Multiplicity of Infection

ChIP:

Chromatin immunoprecipitation

PFA:

Paraformaldehyde

CVD:

Cardiovascular diseases

HF:

Heart failure

FBS:

Fetal bovine serum

References

  1. Ackers-Johnson M, Li PY, Holmes AP, O’Brien SM, Pavlovic D, Foo RS (2016) A simplified, langendorff-free method for concomitant isolation of viable cardiac myocytes and nonmyocytes from the adult mouse heart. Circ Res 119:909–920. https://doi.org/10.1161/CIRCRESAHA.116.309202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bennett CG, Riemondy K, Chapnick DA, Bunker E, Liu X, Kuersten S, Yi R (2016) Genome-wide analysis of Musashi-2 targets reveals novel functions in governing epithelial cell migration. Nucleic Acids Res 44:3788–3800. https://doi.org/10.1093/nar/gkw207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bhattacharjee A, Hasanain M, Kathuria M, Singh A, Datta D, Sarkar J, Mitra K (2018) Ormeloxifene-induced unfolded protein response contributes to autophagy-associated apoptosis via disruption of Akt/mTOR and activation of JNK. Sci Rep 8:2303. https://doi.org/10.1038/s41598-018-20541-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chang KT, Cheng CF, King PC, Liu SY, Wang GS (2017) CELF1 Mediates connexin 43 mRNA degradation in dilated cardiomyopathy. Circ Res 121:1140–1152. https://doi.org/10.1161/CIRCRESAHA.117.311281

    Article  CAS  PubMed  Google Scholar 

  5. Chen S, Zhou Y, Chen Y, Gu J (2018) fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34:i884–i890. https://doi.org/10.1093/bioinformatics/bty560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Choudhury NR, de Lima AF, de Andres-Aguayo L, Graf T, Caceres JF, Rappsilber J, Michlewski G (2013) Tissue-specific control of brain-enriched miR-7 biogenesis. Genes Dev 27:24–38. https://doi.org/10.1101/gad.199190.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Corbett AH (2018) Post-transcriptional regulation of gene expression and human disease. Curr Opin Cell Biol 52:96–104. https://doi.org/10.1016/j.ceb.2018.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Frangogiannis NG (2021) Cardiac fibrosis. Cardiovasc Res 117:1450–1488. https://doi.org/10.1093/cvr/cvaa324

    Article  CAS  PubMed  Google Scholar 

  9. Franklin S, Kimball T, Rasmussen TL, Rosa-Garrido M, Chen H, Tran T, Miller MR, Gray R, Jiang S, Ren S, Wang Y, Tucker HO, Vondriska TM (2016) The chromatin-binding protein Smyd1 restricts adult mammalian heart growth. Am J Physiol Heart Circ Physiol 311:H1234–H1247. https://doi.org/10.1152/ajpheart.00235.2016

    Article  PubMed  PubMed Central  Google Scholar 

  10. Froese N, Cordero J, Abouissa A, Trogisch FA, Grein S, Szaroszyk M, Wang Y, Gigina A, Korf-Klingebiel M, Bosnjak B, Davenport CF, Wiehlmann L, Geffers R, Riechert E, Jurgensen L, Boileau E, Lin Y, Dieterich C, Forster R, Bauersachs J, Ola R, Dobreva G, Volkers M, Heineke J (2022) Analysis of myocardial cellular gene expression during pressure overload reveals matrix based functional intercellular communication. IScience 25:103965. https://doi.org/10.1016/j.isci.2022.103965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gao C, Wang Y (2020) mRNA metabolism in cardiac development and disease: life after transcription. Physiol Rev 100:673–694. https://doi.org/10.1152/physrev.00007.2019

    Article  CAS  PubMed  Google Scholar 

  12. Gao J, Schatton D, Martinelli P, Hansen H, Pla-Martin D, Barth E, Becker C, Altmueller J, Frommolt P, Sardiello M, Rugarli EI (2014) CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins. J Cell Biol 207:213–223. https://doi.org/10.1083/jcb.201403129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guo QQ, Gao J, Wang XW, Yin XL, Zhang SC, Li X, Chi LL, Zhou XM, Wang Z, Zhang QY (2020) RNA-binding protein MSI2 binds to miR-301a-3p and facilitates its distribution in mitochondria of endothelial cells. Front Mol Biosci 7:609828. https://doi.org/10.3389/fmolb.2020.609828

    Article  CAS  PubMed  Google Scholar 

  14. Gupta SK, Garg A, Avramopoulos P, Engelhardt S, Streckfuss-Bomeke K, Batkai S, Thum T (2019) miR-212/132 cluster modulation prevents doxorubicin-mediated atrophy and cardiotoxicity. Mol Ther 27:17–28. https://doi.org/10.1016/j.ymthe.2018.11.004

    Article  CAS  PubMed  Google Scholar 

  15. Hentze MW, Castello A, Schwarzl T, Preiss T (2018) A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol 19:327–341. https://doi.org/10.1038/nrm.2017.130

    Article  CAS  PubMed  Google Scholar 

  16. Katz Y, Li F, Lambert NJ, Sokol ES, Tam WL, Cheng AW, Airoldi EM, Lengner CJ, Gupta PB, Yu Z, Jaenisch R, Burge CB (2014) Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state. Elife 3:e03915. https://doi.org/10.7554/eLife.03915

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kharas MG, Lengner CJ (2017) Stem cells, cancer, and musashi in blood and guts. Trends Cancer 3:347–356. https://doi.org/10.1016/j.trecan.2017.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim D, Paggi JM, Park C, Bennett C, Salzberg SL (2019) Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol 37:907–915. https://doi.org/10.1038/s41587-019-0201-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kimura T, Ferran B, Tsukahara Y, Shang Q, Desai S, Fedoce A, Pimentel DR, Luptak I, Adachi T, Ido Y, Matsui R, Bachschmid MM (2019) Production of adeno-associated virus vectors for in vitro and in vivo applications. Sci Rep 9:13601. https://doi.org/10.1038/s41598-019-49624-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li M, Li AQ, Zhou SL, Lv H, Wei P, Yang WT (2020) RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer. J Exp Clin Cancer Res 39:92. https://doi.org/10.1186/s13046-020-01587-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li X, La Salvia S, Liang Y, Adamiak M, Kohlbrenner E, Jeong D, Chepurko E, Ceholski D, Lopez-Gordo E, Yoon S, Mathiyalagan P, Agarwal N, Jha D, Lodha S, Daaboul G, Phan A, Raisinghani N, Zhang S, Zangi L, Gonzalez-Kozlova E, Dubois N, Dogra N, Hajjar RJ, Sahoo S (2023) Extracellular vesicle-encapsulated adeno-associated viruses for therapeutic gene delivery to the heart. Circulation 148:405–425. https://doi.org/10.1161/CIRCULATIONAHA.122.063759

    Article  PubMed  Google Scholar 

  22. Nakamura M, Okano H, Blendy JA, Montell C (1994) Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development. Neuron 13:67–81. https://doi.org/10.1016/0896-6273(94)90460-x

    Article  CAS  PubMed  Google Scholar 

  23. Oka SI, Sabry AD, Horiuchi AK, Cawley KM, O’Very SA, Zaitsev MA, Shankar TS, Byun J, Mukai R, Xu X, Torres NS, Kumar A, Yazawa M, Ling J, Taleb I, Saijoh Y, Drakos SG, Sadoshima J, Warren JS (2020) Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1. PLoS ONE 15:e0234913. https://doi.org/10.1371/journal.pone.0234913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Paulus MG, Renner K, Nickel AG, Brochhausen C, Limm K, Zugner E, Baier MJ, Pabel S, Wallner S, Birner C, Luchner A, Magnes C, Oefner PJ, Stark KJ, Wagner S, Maack C, Maier LS, Streckfuss-Bomeke K, Sossalla S, Dietl A (2022) Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions. Basic Res Cardiol 117:45. https://doi.org/10.1007/s00395-022-00949-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ (2019) Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med 51:1–13. https://doi.org/10.1038/s12276-019-0355-7

    Article  CAS  PubMed  Google Scholar 

  26. Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33:290–295. https://doi.org/10.1038/nbt.3122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pun-Garcia A, Clemente-Moragon A, Villena-Gutierrez R, Gomez M, Sanz-Rosa D, Diaz-Guerra A, Prados B, Medina JP, Monto F, Ivorra MD, Marquez-Lopez C, Cannavo A, Bernal JA, Koch WJ, Fuster V, de la Pompa JL, Oliver E, Ibanez B (2022) Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics. Basic Res Cardiol 117:62. https://doi.org/10.1007/s00395-022-00966-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Riechert E, Kmietczyk V, Stein F, Schwarzl T, Sekaran T, Jurgensen L, Kamuf-Schenk V, Varma E, Hofmann C, Rettel M, Gur K, Olschlager J, Kuhl F, Martin J, Ramirez-Pedraza M, Fernandez M, Doroudgar S, Mendez R, Katus HA, Hentze MW, Volkers M (2021) Identification of dynamic RNA-binding proteins uncovers a Cpeb4-controlled regulatory cascade during pathological cell growth of cardiomyocytes. Cell Rep 35:109100. https://doi.org/10.1016/j.celrep.2021.109100

    Article  CAS  PubMed  Google Scholar 

  29. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, Bonny A, Brauer M, Brodmann M, Cahill TJ, Carapetis J, Catapano AL, Chugh SS, Cooper LT, Coresh J, Criqui M, DeCleene N, Eagle KA, Emmons-Bell S, Feigin VL, Fernandez-Sola J, Fowkes G, Gakidou E, Grundy SM, He FJ, Howard G, Hu F, Inker L, Karthikeyan G, Kassebaum N, Koroshetz W, Lavie C, Lloyd-Jones D, Lu HS, Mirijello A, Temesgen AM, Mokdad A, Moran AE, Muntner P, Narula J, Neal B, Ntsekhe M, Moraes de Oliveira G, Otto C, Owolabi M, Pratt M, Rajagopalan S, Reitsma M, Ribeiro ALP, Rigotti N, Rodgers A, Sable C, Shakil S, Sliwa-Hahnle K, Stark B, Sundstrom J, Timpel P, Tleyjeh IM, Valgimigli M, Vos T, Whelton PK, Yacoub M, Zuhlke L, Murray C, Fuster V, Group G-N-JGBoCDW (2020) Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD study. J Am Coll Cardiol. 76(2982):3021. https://doi.org/10.1016/j.jacc.2020.11.010

    Article  Google Scholar 

  30. Sabater-Arcis M, Bargiela A, Moreno N, Poyatos-Garcia J, Vilchez JJ, Artero R (2021) Musashi-2 contributes to myotonic dystrophy muscle dysfunction by promoting excessive autophagy through miR-7 biogenesis repression. Mol Ther Nucleic Acids 25:652–667. https://doi.org/10.1016/j.omtn.2021.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sabbah HN (2020) Targeting the mitochondria in heart failure: a translational perspective. JACC Basic Transl Sci 5:88–106. https://doi.org/10.1016/j.jacbts.2019.07.009

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sakakibara S, Imai T, Hamaguchi K, Okabe M, Aruga J, Nakajima K, Yasutomi D, Nagata T, Kurihara Y, Uesugi S, Miyata T, Ogawa M, Mikoshiba K, Okano H (1996) Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 176:230–242. https://doi.org/10.1006/dbio.1996.0130

    Article  CAS  PubMed  Google Scholar 

  33. Sakakibara S, Nakamura Y, Satoh H, Okano H (2001) Rna-binding protein Musashi2: developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS. J Neurosci 21:8091–8107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Scarpulla RC (2012) Nucleus-encoded regulators of mitochondrial function: integration of respiratory chain expression, nutrient sensing and metabolic stress. Biochim Biophys Acta 1819:1088–1097. https://doi.org/10.1016/j.bbagrm.2011.10.011

    Article  CAS  PubMed  Google Scholar 

  35. Schatton D, Pla-Martin D, Marx MC, Hansen H, Mourier A, Nemazanyy I, Pessia A, Zentis P, Corona T, Kondylis V, Barth E, Schauss AC, Velagapudi V, Rugarli EI (2017) CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs. J Cell Biol 216:675–693. https://doi.org/10.1083/jcb.201607019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schimmel K, Jung M, Foinquinos A, Jose GS, Beaumont J, Bock K, Grote-Levi L, Xiao K, Bar C, Pfanne A, Just A, Zimmer K, Ngoy S, Lopez B, Ravassa S, Samolovac S, Janssen-Peters H, Remke J, Scherf K, Dangwal S, Piccoli MT, Kleemiss F, Kreutzer FP, Kenneweg F, Leonardy J, Hobuss L, Santer L, Do QT, Geffers R, Braesen JH, Schmitz J, Brandenberger C, Muller DN, Wilck N, Kaever V, Bahre H, Batkai S, Fiedler J, Alexander KM, Wertheim BM, Fisch S, Liao R, Diez J, Gonzalez A, Thum T (2020) Natural compound library screening identifies new molecules for the treatment of cardiac fibrosis and diastolic dysfunction. Circulation 141:751–767. https://doi.org/10.1161/CIRCULATIONAHA.119.042559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schoenberg DR, Maquat LE (2012) Regulation of cytoplasmic mRNA decay. Nat Rev Genet 13:246–259. https://doi.org/10.1038/nrg3160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shi R, Ying S, Li Y, Zhu L, Wang X, Jin H (2021) Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics. Cell Death Dis 12:346. https://doi.org/10.1038/s41419-021-03625-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Suresh Babu S, Joladarashi D, Jeyabal P, Thandavarayan RA, Krishnamurthy P (2015) RNA-stabilizing proteins as molecular targets in cardiovascular pathologies. Trends Cardiovasc Med 25:676–683. https://doi.org/10.1016/j.tcm.2015.02.006

    Article  CAS  PubMed  Google Scholar 

  40. Warren JS, Tracy CM, Miller MR, Makaju A, Szulik MW, Oka SI, Yuzyuk TN, Cox JE, Kumar A, Lozier BK, Wang L, Llana JG, Sabry AD, Cawley KM, Barton DW, Han YH, Boudina S, Fiehn O, Tucker HO, Zaitsev AV, Franklin S (2018) Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart. Proc Natl Acad Sci USA 115:E7871–E7880. https://doi.org/10.1073/pnas.1800680115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang D, Liu HQ, Liu FY, Guo Z, An P, Wang MY, Yang Z, Fan D, Tang QZ (2021) Mitochondria in pathological cardiac hypertrophy research and therapy. Front Cardiovasc Med 8:822969. https://doi.org/10.3389/fcvm.2021.822969

    Article  CAS  PubMed  Google Scholar 

  42. Yang W, Yang L, Wang J, Zhang Y, Li S, Yin Q, Suo J, Ma R, Ye Y, Cheng H, Li J, Hui J, Hu P (2022) Msi2-mediated MiR7a-1 processing repression promotes myogenesis. J Cachexia Sarcopenia Muscle 13:728–742. https://doi.org/10.1002/jcsm.12882

    Article  PubMed  Google Scholar 

  43. Zhang Y, Si Y, Ma N, Mei J (2015) The RNA-binding protein PCBP2 inhibits Ang II-induced hypertrophy of cardiomyocytes though promoting GPR56 mRNA degeneration. Biochem Biophys Res Commun 464:679–684. https://doi.org/10.1016/j.bbrc.2015.06.139

    Article  CAS  PubMed  Google Scholar 

  44. Zhou A, Shi G, Kang GJ, Xie A, Liu H, Jiang N, Liu M, Jeong EM, Dudley SC Jr (2018) RNA binding protein, hur, regulates SCN5A expression through stabilizing MEF2C transcription factor mRNA. J Am Heart Assoc. https://doi.org/10.1161/JAHA.117.007802

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We want to thank Dr. Rajdeep Guha, Head of Animal Facility, CSIR-CDRI, for his help with animal experiments. We want to thank Director CSIR-CDRI, Dr. Manoj Kumar Barthwal, Dr. Amit Lahiri, Dr. Chandra Prakash Pandey, Dr. Hobby Aggarwal, Dr. Jayanta Sarkar, and Mr. Ajay Singh from CSIR-CDRI, for their help with the instruments and training. We acknowledge the FACS facility, CSIR-CDRI. We acknowledge the valuable suggestions of Dr. Regalla Kumarswamy, CSIR- Centre for Cellular and Molecular Biology, Hyderabad, India, Dr. Marisol Ruiz- Meana, Valld’Hebron Hospital Universitari, Barcelona, Spain, and Dr. Gaurav Ahuja, Indraprastha Institute of Information Technology, Delhi, India. This manuscript has CSIR-CDRI communication number 10680.

Funding

This work was funded by Ramalingaswami Re-entry Fellowship (BT/RLF/re-entry/14/2019) from the Department of Biotechnology, Government of India, and MLP0008 & OLP0101 from CSIR-CDRI, Lucknow to SKG. SS, SP, SK, and RKS avail JRF fellowship from CSIR (Council of Scientific and Industrial Research), Government of India. RK avails SRF fellowship from ICMR (Indian Council of Medical Research), and AG and ADC avail JRF fellowship from UGC (University Grant Commission), Government of India.

Author information

Author notes

  1. Aakash Gaur, Rakesh Kumar Sharma and Renu Kumari have equal contribution to this work.

Authors and Affiliations

  1. Pharmacology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, India, 226031

    Sandhya Singh, Aakash Gaur, Renu Kumari, Shakti Prakash, Sunaina Kumari, Ayushi Devendrasingh Chaudhary, Pankaj Prasun, Kumaravelu Jagavelu, Pragya Bharati, Kashif Hanif & Shashi Kumar Gupta

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

    Aakash Gaur, Rakesh Kumar Sharma, Renu Kumari, Shakti Prakash, Ayushi Devendrasingh Chaudhary, Priyanka Pant, Kumaravelu Jagavelu, Pragya Bharati, Kashif Hanif, Kalyan Mitra & Shashi Kumar Gupta

  3. Division of Sophisticated Analytical Instrument Facility and Research, CSIR-Central Drug Research Institute, Lucknow, India

    Rakesh Kumar Sharma & Kalyan Mitra

  4. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India

    Priyanka Pant

  5. Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany

    Hannah Hunkler & Thomas Thum

  6. Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany

    Thomas Thum

  7. National Institute of Plant Genome Research, New Delhi, India

    Pragya Chitkara & Shailesh Kumar

Authors
  1. Sandhya Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aakash Gaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rakesh Kumar Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renu Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shakti Prakash
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sunaina Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ayushi Devendrasingh Chaudhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pankaj Prasun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Priyanka Pant
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hannah Hunkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Thum
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kumaravelu Jagavelu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pragya Bharati
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kashif Hanif
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Pragya Chitkara
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shailesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kalyan Mitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Shashi Kumar Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SKG has developed the concept, designed the study, planned experiments, analyzed results, and prepared the manuscript. SS designed the study, performed most experiments, analyzed the results, and drafted the manuscript. AG, RK, SP, SK, ADC, and PP helped with neonatal rat cardiomyocyte isolation, lentivirus, and AAV production. RKS and KM performed electron microscopy experiments on heart samples. PP and KJ helped with echocardiography and animal experiments. PB and KH provided the rat TAC heart samples. PC and SK performed the RNA sequencing analysis. TT and HH gave critical inputs and provided cardiac fractionation data.

Corresponding author

Correspondence to Shashi Kumar Gupta.

Ethics declarations

Conflict of interest

Authors declare no conflict of interest.

Informed consent

TT has filed and licensed patents about non-coding RNAs and is the founder and shareholder of Cardior Pharmaceuticals GmbH (outside of this manuscript). SKG holds patents about non-coding RNAs (outside of this manuscript).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the topical collection “Mitochondria at the heart of cardioprotection”.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3180 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, S., Gaur, A., Sharma, R.K. et al. Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA. Basic Res Cardiol 118, 46 (2023). https://doi.org/10.1007/s00395-023-01016-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-023-01016-y

Keywords

Search

Navigation