{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T02:39:41Z","timestamp":1793327981246,"version":"4.5.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hypertension, exercise, and pregnancy are common triggers of cardiac remodeling, which occurs primarily through the hypertrophy of individual cardiomyocytes. During hypertrophy, stress-induced signal transduction increases cardiomyocyte transcription and translation, which promotes the addition of new contractile units through poorly understood mechanisms. The cardiomyocyte microtubule network is also implicated in hypertrophy, but via an unknown role. Here, we show that microtubules are indispensable for cardiac growth via spatiotemporal control of the translational machinery. We find that the microtubule motor Kinesin-1 distributes mRNAs and ribosomes along microtubule tracks to discrete domains within the cardiomyocyte. Upon hypertrophic stimulation, microtubules redistribute mRNAs and new protein synthesis to sites of growth at the cell periphery. If the microtubule network is disrupted, mRNAs and ribosomes collapse around the nucleus, which results in mislocalized protein synthesis, the rapid degradation of new proteins, and a failure of growth, despite normally increased translation rates. Together, these data indicate that mRNAs and ribosomes are actively transported to specific sites to facilitate local translation and assembly of contractile units, and suggest that properly localized translation \u2013 and not simply translation rate \u2013 is a critical determinant of cardiac hypertrophy. In this work, we find that microtubule based-transport is essential to couple augmented transcription and translation to productive cardiomyocyte growth during cardiac stress.<\/jats:p>","DOI":"10.1038\/s41467-021-21685-4","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T06:03:49Z","timestamp":1615442629000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["Microtubules orchestrate local translation to enable cardiac growth"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-9731","authenticated-orcid":false,"given":"Emily A.","family":"Scarborough","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8458-9796","authenticated-orcid":false,"given":"Keita","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-522X","authenticated-orcid":false,"given":"Noa","family":"Erlitzki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghana","family":"Iyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Aung","family":"Phyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Bogush","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4388-1579","authenticated-orcid":false,"given":"Izhak","family":"Kehat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-9131","authenticated-orcid":false,"given":"Benjamin L.","family":"Prosser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"21685_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","volume":"15","author":"M Nakamura","year":"2018","unstructured":"Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387\u2013407 (2018).","journal-title":"Nat. Rev. Cardiol."},{"key":"21685_CR2","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1161\/01.CIR.0000120390.68287.BB","volume":"109","author":"N Frey","year":"2004","unstructured":"Frey, N., Katus, H. A., Olson, E. N. & Hill, J. A. Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580\u20131589 (2004).","journal-title":"Circulation"},{"key":"21685_CR3","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1172\/JCI62839","volume":"123","author":"JH van Berlo","year":"2013","unstructured":"van Berlo, J. H., Maillet, M. & Molkentin, J. D. Signaling effectors underlying pathologic growth and remodeling of the heart. J. Clin. Invest. 123, 37\u201345 (2013).","journal-title":"J. Clin. Invest."},{"key":"21685_CR4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.yjmcc.2018.01.012","volume":"116","author":"YE Lewis","year":"2018","unstructured":"Lewis, Y. E. et al. Localization of transcripts, translation, and degradation for spatiotemporal sarcomere maintenance. J. Mol. Cell Cardiol. 116, 16\u201328 (2018).","journal-title":"J. Mol. Cell Cardiol."},{"key":"21685_CR5","doi-asserted-by":"publisher","first-page":"25126","DOI":"10.1073\/pnas.1904385116","volume":"116","author":"F Rudolph","year":"2019","unstructured":"Rudolph, F. et al. Resolving titin\u2019s lifecycle and the spatial organization of protein turnover in mouse cardiomyocytes. Proc. Natl Acad. Sci. USA 116, 25126\u201325136 (2019).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"21685_CR6","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1126\/science.8097594","volume":"260","author":"H Tsutsui","year":"1993","unstructured":"Tsutsui, H., Ishihara, K. & Cooper, G. Cytoskeletal role in the contractile dysfunction of hypertrophied myocardium. Science 260, 682\u2013687 (1993).","journal-title":"Science"},{"key":"21685_CR7","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1038\/s41591-018-0046-2","volume":"24","author":"CY Chen","year":"2018","unstructured":"Chen, C. Y. et al. Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nat. Med. 24, 1225\u20131233 (2018).","journal-title":"Nat. Med."},{"key":"21685_CR8","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1152\/japplphysiol.00744.2002","volume":"94","author":"BS Scopacasa","year":"2003","unstructured":"Scopacasa, B. S., Teixeira, V. P. & Franchini, K. G. Colchicine attenuates left ventricular hypertrophy but preserves cardiac function of aortic-constricted rats. J. Appl. Physiol. 94, 1627\u20131633 (2003).","journal-title":"J. Appl. Physiol."},{"key":"21685_CR9","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1006\/jmcc.1999.0953","volume":"31","author":"H Tsutsui","year":"1999","unstructured":"Tsutsui, H. et al. Chronic colchicine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats. J. Mol. Cell Cardiol. 31, 1203\u20131213 (1999).","journal-title":"J. Mol. Cell Cardiol."},{"key":"21685_CR10","doi-asserted-by":"publisher","first-page":"H523","DOI":"10.1152\/ajpheart.00462.2009","volume":"297","author":"JT Fassett","year":"2009","unstructured":"Fassett, J. T. et al. Adenosine regulation of microtubule dynamics in cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 297, H523\u2013H532 (2009).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"21685_CR11","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1042\/BJ20041888","volume":"388","author":"M Rolfe","year":"2005","unstructured":"Rolfe, M., McLeod, L. E., Pratt, P. F. & Proud, C. G. Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). Biochem. J. 388, 973\u2013984 (2005).","journal-title":"Biochem. J."},{"key":"21685_CR12","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.ceb.2018.10.003","volume":"56","author":"I Gasic","year":"2019","unstructured":"Gasic, I. & Mitchison, T. J. Autoregulation and repair in microtubule homeostasis. Curr. Opin. Cell Biol. 56, 80\u201387 (2019).","journal-title":"Curr. Opin. Cell Biol."},{"key":"21685_CR13","doi-asserted-by":"publisher","first-page":"e10","DOI":"10.1161\/CIRCRESAHA.119.315582","volume":"126","author":"J Heffler","year":"2020","unstructured":"Heffler, J. et al. A balance between intermediate filaments and microtubules maintains nuclear architecture in the cardiomyocyte. Circ. Res. 126, e10\u2013e26 (2020).","journal-title":"Circ. Res."},{"key":"21685_CR14","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.yjmcc.2016.04.015","volume":"97","author":"BG Reid","year":"2016","unstructured":"Reid, B. G. et al. Discovery of novel small molecule inhibitors of cardiac hypertrophy using high throughput, high content imaging. J. Mol. Cell Cardiol. 97, 106\u2013113 (2016).","journal-title":"J. Mol. Cell Cardiol."},{"key":"21685_CR15","doi-asserted-by":"publisher","first-page":"660","DOI":"10.2353\/ajpath.2010.090348","volume":"176","author":"M Yoshida","year":"2010","unstructured":"Yoshida, M. et al. Weaving hypothesis of cardiomyocyte sarcomeres: discovery of periodic broadening and narrowing of intercalated disk during volume-load change. Am. J. Pathol. 176, 660\u2013678 (2010).","journal-title":"Am. J. Pathol."},{"key":"21685_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/srep20674","volume":"6","author":"H Yang","year":"2016","unstructured":"Yang, H. et al. Dynamic myofibrillar remodeling in live cardiomyocytes under static stretch. Sci. Rep. 6, 20674 (2016).","journal-title":"Sci. Rep."},{"key":"21685_CR17","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.molcel.2018.07.001","volume":"71","author":"S Juszkiewicz","year":"2018","unstructured":"Juszkiewicz, S. & Hegde, R. S. Quality control of orphaned proteins. Mol. Cell 71, 443\u2013457 (2018).","journal-title":"Mol. Cell"},{"key":"21685_CR18","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0955-0674(99)00058-7","volume":"12","author":"BL Goode","year":"2000","unstructured":"Goode, B. L., Drubin, D. G. & Barnes, G. Functional cooperation between the microtubule and actin cytoskeletons. Curr. Opin. Cell Biol. 12, 63\u201371 (2000).","journal-title":"Curr. Opin. Cell Biol."},{"key":"21685_CR19","first-page":"261","volume":"106","author":"FC Ferguson","year":"1952","unstructured":"Ferguson, F. C. Colchicine. I. General pharmacology. J. Pharm. Exp. Ther. 106, 261\u2013270 (1952).","journal-title":"J. Pharm. Exp. Ther."},{"key":"21685_CR20","first-page":"605","volume":"192","author":"AL Hunter","year":"1975","unstructured":"Hunter, A. L. & Klaassen, C. D. Biliary excretion of colchicine. J. Pharm. Exp. Ther. 192, 605\u2013617 (1975).","journal-title":"J. Pharm. Exp. Ther."},{"key":"21685_CR21","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.neuron.2004.07.022","volume":"43","author":"Y Kanai","year":"2004","unstructured":"Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43, 513\u2013525 (2004).","journal-title":"Neuron"},{"key":"21685_CR22","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1002\/(SICI)1097-0169(1997)38:4<318::AID-CM2>3.0.CO;2-#","volume":"38","author":"JH Carson","year":"1997","unstructured":"Carson, J. H., Worboys, K., Ainger, K. & Barbarese, E. Translocation of myelin basic protein mRNA in oligodendrocytes requires microtubules and kinesin. Cell Motil. Cytoskeleton 38, 318\u2013328 (1997).","journal-title":"Cell Motil. Cytoskeleton"},{"key":"21685_CR23","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1093\/cvr\/cvm048","volume":"77","author":"SY Boateng","year":"2008","unstructured":"Boateng, S. Y. & Goldspink, P. H. Assembly and maintenance of the sarcomere night and day. Cardiovasc. Res. 77, 667\u2013675 (2008).","journal-title":"Cardiovasc. Res."},{"key":"21685_CR24","doi-asserted-by":"publisher","first-page":"C50","DOI":"10.1152\/ajpcell.1979.237.1.C50","volume":"237","author":"BR Eisenberg","year":"1979","unstructured":"Eisenberg, B. R., Mathias, R. T. & Gilai, A. Intracellular localization of markers within injected or cut frog muscle fibers. Am. J. Physiol. 237, C50\u2013C55 (1979).","journal-title":"Am. J. Physiol."},{"key":"21685_CR25","doi-asserted-by":"publisher","first-page":"4910","DOI":"10.1073\/pnas.84.14.4910","volume":"84","author":"K Luby-Phelps","year":"1987","unstructured":"Luby-Phelps, K., Castle, P. E., Taylor, D. L. & Lanni, F. Hindered diffusion of inert tracer particles in the cytoplasm of mouse 3T3 cells. Proc. Natl Acad. Sci. USA 84, 4910\u20134913 (1987).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"21685_CR26","doi-asserted-by":"publisher","first-page":"3263","DOI":"10.1242\/dev.078626","volume":"139","author":"C Medioni","year":"2012","unstructured":"Medioni, C., Mowry, K. & Besse, F. Principles and roles of mRNA localization in animal development. Development 139, 3263\u20133276 (2012).","journal-title":"Development"},{"key":"21685_CR27","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1242\/jcs.02371","volume":"118","author":"LA Mingle","year":"2005","unstructured":"Mingle, L. A. et al. Localization of all seven messenger RNAs for the actin-polymerization nucleator Arp2\/3 complex in the protrusions of fibroblasts. J. Cell Sci. 118, 2425\u20132433 (2005).","journal-title":"J. Cell Sci."},{"key":"21685_CR28","doi-asserted-by":"publisher","first-page":"e1001208","DOI":"10.1371\/journal.pgen.1001208","volume":"6","author":"Y Rui","year":"2010","unstructured":"Rui, Y., Bai, J. & Perrimon, N. Sarcomere formation occurs by the assembly of multiple latent protein complexes. PLoS Genet. 6, e1001208 (2010).","journal-title":"PLoS Genet."},{"key":"21685_CR29","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1083\/jcb.117.5.1007","volume":"117","author":"MH Lu","year":"1992","unstructured":"Lu, M. H. et al. The vinculin\/sarcomeric-alpha-actinin\/alpha-actin nexus in cultured cardiac myocytes. J. Cell Biol. 117, 1007\u20131022 (1992).","journal-title":"J. Cell Biol."},{"key":"21685_CR30","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/0092-8674(80)90331-1","volume":"20","author":"AB Fulton","year":"1980","unstructured":"Fulton, A. B., Wan, K. M. & Penman, S. The spatial distribution of polyribosomes in 3T3 cells and the associated assembly of proteins into the skeletal framework. Cell 20, 849\u2013857 (1980).","journal-title":"Cell"},{"key":"21685_CR31","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1242\/jcs.105.4.867","volume":"105","author":"AB Fulton","year":"1993","unstructured":"Fulton, A. B. & L\u2019Ecuyer, T. Cotranslational assembly of some cytoskeletal proteins: implications and prospects. J. Cell Sci. 105, 867\u2013871 (1993).","journal-title":"J. Cell Sci."},{"key":"21685_CR32","doi-asserted-by":"publisher","first-page":"H2072","DOI":"10.1152\/ajpheart.00396.2003","volume":"285","author":"M Takahashi","year":"2003","unstructured":"Takahashi, M. et al. Phenotypic consequences of beta1-tubulin expression and MAP4 decoration of microtubules in adult cardiocytes. Am. J. Physiol. Heart Circ. Physiol. 285, H2072\u2013H2083 (2003).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"21685_CR33","doi-asserted-by":"publisher","first-page":"H1135","DOI":"10.1152\/ajpheart.01275.2007","volume":"294","author":"D Scholz","year":"2008","unstructured":"Scholz, D. et al. Microtubule-dependent distribution of mRNA in adult cardiocytes. Am. J. Physiol. Heart Circ. Physiol. 294, H1135\u2013H1144 (2008).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"21685_CR34","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1016\/j.bpj.2014.05.008","volume":"106","author":"N Kaul","year":"2014","unstructured":"Kaul, N., Soppina, V. & Verhey, K. J. Effects of \u03b1-tubulin K40 acetylation and detyrosination on kinesin-1 motility in a purified system. Biophys. J. 106, 2636\u20132643 (2014).","journal-title":"Biophys. J."},{"key":"21685_CR35","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1083\/jcb.201608022","volume":"216","author":"K Yasuda","year":"2017","unstructured":"Yasuda, K., Clatterbuck-Soper, S. F., Jackrel, M. E., Shorter, J. & Mili, S. FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination. J. Cell Biol. 216, 1015\u20131034 (2017).","journal-title":"J. Cell Biol."},{"key":"21685_CR36","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1161\/CIRCULATIONAHA.113.008452","volume":"129","author":"C Zhang","year":"2014","unstructured":"Zhang, C. et al. Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure. Circulation 129, 1742\u20131750 (2014).","journal-title":"Circulation"},{"key":"21685_CR37","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0003-2697(79)90568-2","volume":"96","author":"RE Ostlund","year":"1979","unstructured":"Ostlund, R. E., Leung, J. T. & Hajek, S. V. Biochemical determination of tubulin-microtubule equilibrium in cultured cells. Anal. Biochem. 96, 155\u2013164 (1979).","journal-title":"Anal. Biochem."},{"key":"21685_CR38","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1161\/01.RES.77.6.1040","volume":"77","author":"J Sadoshima","year":"1995","unstructured":"Sadoshima, J. & Izumo, S. Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ. Res. 77, 1040\u20131052 (1995).","journal-title":"Circ. Res."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-21685-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-21685-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-21685-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T06:14:25Z","timestamp":1669961665000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-21685-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,11]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["21685"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-21685-4","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,11]]},"assertion":[{"value":"23 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1547"}}