Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure


Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40–50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Proteomic analysis of human left ventricular tissues of varying disease severity and etiology.
Fig. 2: Characterization of microtubules and desmin in non-failing and failing human myocytes.
Fig. 3: Microtubule-dependent viscoelasticity of human myocytes measured via nanoindentation.
Fig. 4: Suppression of detyrosinated microtubules improves contractility in failing human cardiomyocytes.
Fig. 5: Genetic modification of tubulin tyrosination reduces stiffness and improves contractility.


  1. 1.

    Tsutsui, H., Ishihara, K. & Cooper, G. Cytoskeletal role in the contractile dysfunction of hypertrophied myocardium. Science 260, 682–687 (1993).

    CAS  Article  Google Scholar 

  2. 2.

    Collins, J. F. et al. The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J. Mol. Cell. Cardiol. 28, 1435–1443 (1996).

    CAS  Article  Google Scholar 

  3. 3.

    Tagawa, H. et al. Cytoskeletal role in the transition from compensated to decompensated hypertrophy during adult canine left ventricular pressure overloading. Cir. Res. 82, 751–761 (1998).

    CAS  Article  Google Scholar 

  4. 4.

    Ishibashi, Y. et al. Role of microtubules in myocyte contractile dysfunction during cardiac hypertrophy in the rat. Am. J. Physiol. 271, H1978–87 (1996).

    CAS  PubMed  Google Scholar 

  5. 5.

    Bailey, B. A., Dipla, K., Li, S. & Houser, S. R. Cellular basis of contractile derangements of hypertrophied feline ventricular myocytes. J. Mol. Cell. Cardiol. 29, 1823–1835 (1997).

    CAS  Article  Google Scholar 

  6. 6.

    Kerr, J. P. et al. Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle. Nat. Commun. 6, 8526 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Robison, P. et al. Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes. Science 352, aaf0659 (2016).

    Article  Google Scholar 

  8. 8.

    Robison, P. & Prosser, B. L. Microtubule mechanics in the working myocyte. J. Physiol. 595, 3931–3937 (2017).

    CAS  Article  Google Scholar 

  9. 9.

    Agnetti, G. et al. Desmin modifications associate with amyloid-like oligomers deposition in heart failure. Cardiovasc. Res. 102, 24–34 (2014).

    CAS  Article  Google Scholar 

  10. 10.

    Burke, M. A. et al. Molecular profiling of dilated cardiomyopathy that progresses to heart failure. JCI Insight 1, e86898 (2016).

    Article  Google Scholar 

  11. 11.

    Chen, J., Bardes, E. E., Aronow, B. J. & Jegga, A. G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 37, W305–11 (2009).

    CAS  Article  Google Scholar 

  12. 12.

    Frolova, E. G. et al. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload. FASEB J. 26, 2363–2373 (2012).

    CAS  Article  Google Scholar 

  13. 13.

    Wulfkuhle, J. D. et al. Domain analysis of supervillin, an F-actin bundling plasma membrane protein with functional nuclear localization signals. J. Cell Sci. 112, 2125–2136 (1999).

    CAS  PubMed  Google Scholar 

  14. 14.

    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, H2072–83 (2003).

    CAS  Article  Google Scholar 

  15. 15.

    Cheng, G. et al. Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. J. Biol. Chem. 285, 38125–38140 (2010).

    CAS  Article  Google Scholar 

  16. 16.

    Prota, A. E. et al. Structural basis of tubulin tyrosination by tubulin tyrosine ligase. J. Cell Biol. 200, 259–270 (2013).

    CAS  Article  Google Scholar 

  17. 17.

    Prins, K. W. et al. Dystrophin is a microtubule-associated protein. J. Cell Biol. 186, 363–369 (2009).

    CAS  Article  Google Scholar 

  18. 18.

    Caporizzo, M. A. et al. Strain-rate dependence of elastic modulus reveals silver nanoparticle induced cytotoxicity. Nanobiomedicine (Rij) 2, 9 (2015).

    Article  Google Scholar 

  19. 19.

    Gomez, A. M., Kerfant, B. G. & Vassort, G. Microtubule disruption modulates Ca2+ signaling in rat cardiac myocytes. Circ. Res. 86, 30–36 (2000).

    CAS  Article  Google Scholar 

  20. 20.

    Janke, C. & Bulinski, J. C. Post-translational regulation of the microtubule cytoskeleton: Mechanisms and functions. Nat. Rev. Mol. Cell Biol. 12, 773–786 (2011).

    CAS  Article  Google Scholar 

  21. 21.

    Zile, M. R. et al. Cardiocyte cytoskeleton in patients with left ventricular pressure overload hypertrophy. J. Am. Coll. Cardiol. 37, 1080–1084 (2001).

    CAS  Article  Google Scholar 

  22. 22.

    Zhang, C. et al. Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte T-tubule remodeling and Ca2+ handling dysfunction in heart failure. Circulation 129, 1742–1750 (2014).

    CAS  Article  Google Scholar 

  23. 23.

    Stones, R., Benoist, D., Peckham, M. & White, E. Microtubule proliferation in right ventricular myocytes of rats with monocrotaline-induced pulmonary hypertension. J. Mol. Cell. Cardiol. 56, 91–96 (2013).

    CAS  Article  Google Scholar 

  24. 24.

    Prins, K. W. et al. Colchicine depolymerizes microtubules, increases junctophilin-2, and improves right ventricular function in experimental pulmonary arterial hypertension. J. Am. Heart Assoc. 6, e006195 (2017).

    Article  Google Scholar 

  25. 25.

    Lemler, M. S. et al. Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension. Am. J. Physiol. Heart Circ. Physiol. 279, H1365–76 (2000).

    CAS  Article  Google Scholar 

  26. 26.

    Prosser, B. L., Ward, C. W. & Lederer, W. J. X-ROS signaling: Rapid mechano-chemo transduction in heart. Science 333, 1440–1445 (2011).

    CAS  Article  Google Scholar 

  27. 27.

    Prins, K. W., Asp, M. L., Zhang, H., Wang, W. & Metzger, J. M. Microtubule-mediated misregulation of junctophilin-2 underlies T-tubule disruptions and calcium mishandling in mdx mice. JACC: Basic Transl. Sci. 1, 122–130 (2016).

    Google Scholar 

  28. 28.

    Shiels, H. et al. Stable microtubules contribute to cardiac dysfunction in the streptozotocin-induced model of type 1 diabetes in the rat. Mol. Cell. Biochem. 294, 173–180 (2007).

    CAS  Article  Google Scholar 

  29. 29.

    Wang, X., Li, F., Campbell, S. E. & Gerdes, A. M. Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: II. Cytoskeletal remodeling. J. Mol. Cell. Cardiol. 31, 319–331 (1999).

    CAS  Article  Google Scholar 

  30. 30.

    Miragoli, M. et al. Microtubule-dependent mitochondria alignment regulates calcium release in response to nanomechanical stimulus in heart myocytes. Cell Rep. 14, 140–151 (2016).

    CAS  Article  Google Scholar 

  31. 31.

    Rochdi, M., Sabouraud, A., Girre, C., Venet, R. & Scherrmann, J. M. Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects. Eur. J. Clin. Pharmacol. 46, 351–354 (1994).

    CAS  Article  Google Scholar 

  32. 32.

    Terkeltaub, R. A. Clinical practice: gout. N. Engl. J. Med. 349, 1647–1655 (2003).

    CAS  Article  Google Scholar 

  33. 33.

    Yancy, C. W. et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 62, e147–239 (2013).

    Article  Google Scholar 

  34. 34.

    Cuffe, M. S. et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. JAMA 287, 1541–1547 (2002).

    CAS  Article  Google Scholar 

  35. 35.

    Lang, R. M. et al. Recommendations for chamber quantification. Eur. J. Echocardiogr. 7, 79–108 (2006).

    Article  Google Scholar 

  36. 36.

    Dipla, K., Mattiello, J. A., Jeevanandam, V., Houser, S. R. & Margulies, K. B. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation 97, 2316–2322 (1998).

    CAS  Article  Google Scholar 

  37. 37.

    Simithy, J. et al. Characterization of histone acylations links chromatin modifications with metabolism. Nat. Commun. 8, 1141 (2017).

    Article  Google Scholar 

  38. 38.

    Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).

    CAS  Article  Google Scholar 

  39. 39.

    Elias, J. E. & Gygi, S. P. Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat. Methods 4, 207–214 (2007).

    CAS  Article  Google Scholar 

  40. 40.

    Vizcaíno, J. A. et al. 2016 update of the PRIDE database and related tools. Nucleic Acids Res. 44, 447–456 (2016).

    Article  Google Scholar 

Download references


We would like thank the Quantitative Proteomics Resource Core of the Perelman School of Medicine and the Penn Center for Musculoskeletal Disorders Histology Core at the University of Pennsylvania. This work was supported by funding from the National Institutes of Health (NIH) R01-HL133080 to B.L.P. and T32 R05346-09 to P.R., the American Heart Association 17POST33440043 to M.A.C., and by the Center for Engineering MechanoBiology through a grant from the National Science Foundation’s Science and Technology Center program: 15-48571. The procurement of human heart tissue was enabled by grants from the NIH (HL089847 and HL105993) to K.B.M.

Author information




B.L.P., C.Y.C., M.A.C., and K.B.M. designed the study. B.L.P., C.Y.C., M.A.C., K.B., A.V., N.A.K., A.I.B., P.R., J.G.H., and A.K.S. carried out the data acquisition and analysis. M.P.M., C.Y.C., A.B., and B.L.P. carried out the proteomic analysis. B.L.P., C.Y.C., M.A.C., P.R., and K.B.M. interpreted the data. B.L.P. and C.Y.C. prepared the manuscript. All authors participated in the critical review and revision of the manuscript.

Corresponding author

Correspondence to Benjamin L. Prosser.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6

Reporting Summary

Supplementary Tables

Supplementary Tables 1–6

Supplementary Video 1

Skeletonized 3D reconstruction of the microtubule network from Airyscan imaging of a failing human myocyte (DCM) labeled with Tyr-tubulin antibody to demonstrate the density of the microtubule network

Supplementary Video 2

Microtubule buckling in a contracting non-failing myocyte infected with AdV-EMTB for 48 h

Supplementary Video 3

Microtubule buckling in a contracting failing myocyte (DCM) infected with AdV-EMTB for 48 h

Supplementary Data

Spreadsheet of mass spectrometry data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, C.Y., Caporizzo, M.A., Bedi, K. et al. Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nat Med 24, 1225–1233 (2018).

Download citation

Further reading


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing