Pflügers Archiv - European Journal of Physiology

, Volume 469, Issue 12, pp 1603–1613 | Cite as

The naked mole-rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent

  • Kelly M. Grimes
  • David Y. Barefield
  • Mohit Kumar
  • James W. McNamara
  • Susan T. Weintraub
  • Pieter P. de Tombe
  • Sakthivel Sadayappan
  • Rochelle BuffensteinEmail author
Muscle physiology
Part of the following topical collections:
  1. Muscle physiology


The long-lived, hypoxic-tolerant naked mole-rat well-maintains cardiac function over its three-decade-long lifespan and exhibits many cardiac features atypical of similar-sized laboratory rodents. For example, they exhibit low heart rates and resting cardiac contractility, yet have a large cardiac reserve. These traits are considered ecophysiological adaptations to their dank subterranean atmosphere of low oxygen and high carbon dioxide levels and may also contribute to negligible declines in cardiac function during aging. We asked if naked mole-rats had a different myofilament protein signature to that of similar-sized mice that commonly show both high heart rates and high basal cardiac contractility. Adult mouse ventricles predominantly expressed α-myosin heavy chain (97.9 ± 0.4%). In contrast, and more in keeping with humans, β myosin heavy chain was the dominant isoform (79.0 ± 2.0%) in naked mole-rat ventricles. Naked mole-rat ventricles diverged from those of both humans and mice, as they expressed both cardiac and slow skeletal isoforms of troponin I. This myofilament protein profile is more commonly observed in mice in utero and during cardiomyopathies. There were no species differences in phosphorylation of cardiac myosin binding protein-C or troponin I. Phosphorylation of both ventricular myosin light chain 2 and cardiac troponin T in naked mole-rats was approximately half that observed in mice. Myofilament function was also compared between the two species using permeabilized cardiomyocytes. Together, these data suggest a cardiac myofilament protein signature that may contribute to the naked mole-rat’s suite of adaptations to its natural subterranean habitat.


Naked mole-rat Heart Slow skeletal troponin I β myosin heavy chain Neoteny Hypoxia 



This work was supported in part by the following grants: American Heart Association, 12GRNT12030299 and 15GRNT22420022 (R. Buffenstein); National Institutes of Health Training Grant, T32 AG021890 (K.M. Grimes); National Institutes of Health, R01 HL105826 and K02 HL114749 (S. Sadayappan) and the American Heart Association Grant-in-Aid, 14GRNT20490025 (S. Sadayappan); National Institutes of Health, P01 HL62426 and R01 HL75494 (P.P. de Tombe); American Heart Association Midwest Predoctoral Fellowship, 11PRE7240022 (D.Y. Barefield); and National Institutes of Health shared instrumentation grant S10RR025111 (S.T. Weintraub). Mass spectrometry analyses were conducted in the University of Texas Health Science Center at San Antonio Institutional Mass Spectrometry Laboratory; the expert technical assistance of Sammy Pardo is gratefully acknowledged.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

424_2017_2046_MOESM1_ESM.xlsx (124 kb)
Table S1 (XLSX 124 kb)


  1. 1.
    Barefield D, Kumar M, de Tombe PP, Sadayappan S (2014) Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 306:H807–H815CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Barefield D, Kumar M, Gorham J, Seidman JG, Seidman CE, de Tombe PP, Sadayappan S (2014) Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J Mol Cell Cardiol 79C:234–243Google Scholar
  3. 3.
    Barefield D, Sadayappan S (2010) Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J Mol Cell Cardiol 48:866–875CrossRefPubMedGoogle Scholar
  4. 4.
    Bodor GS, Oakeley AE, Allen PD, Crimmins DL, Ladenson JH, Anderson PA (1997) Troponin I phosphorylation in the normal and failing adult human heart. Circulation 96:1495–1500CrossRefPubMedGoogle Scholar
  5. 5.
    Buffenstein R (2000) Ecophysiological responses of subterranean rodents to underground habitats. In: Lacey EA, Patton JL, Cameron GN (eds) Life underground: the biology of subterranean rodents. University of Chicago Press, Chicago, pp 183–226Google Scholar
  6. 6.
    Buffenstein R (1996) Ecophysiological responses to a subterranean habitat; A Bathyergid perspective. Mammalia 60:591–605Google Scholar
  7. 7.
    Buffenstein R (2005) The naked mole-rat: a new long-living model for human aging research. J Gerontol A Biol Sci Med Sci 60:1369–1377CrossRefPubMedGoogle Scholar
  8. 8.
    Buffenstein R (2008) Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B 178:439–445CrossRefPubMedGoogle Scholar
  9. 9.
    Buffenstein R, Yahav S (1991) Is the naked mole-rat Heterocephalus glaber an endothermic yet poikilothermic mammal. J Therm Biol 16:227–232CrossRefGoogle Scholar
  10. 10.
    Chang AN, Battiprolu PK, Cowley PM, Chen G, Gerard RD, Pinto JR, Hill JA, Baker AJ, Kamm KE, Stull JT (2015) Constitutive phosphorylation of cardiac myosin regulatory light chain in vivo. J Biol Chem 290:10703–10716CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Colson BA, Locher MR, Bekyarova T, Patel JR, Fitzsimons DP, Irving TC, Moss RL (2010) Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development. J Physiol 588:981–993CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Edrey YH, Casper D, Huchon D, Mele J, Gelfond JA, Kristan DM, Nevo E, Buffenstein R (2012) Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity. Aging Cell 11:213–222CrossRefPubMedGoogle Scholar
  13. 13.
    Goldman BD, Goldman SL, Lanz T, Magaurin A, Maurice A (1999) Factors influencing metabolic rate in naked mole-rats (Heterocephalus glaber). Physiol Behav 66:447–459CrossRefPubMedGoogle Scholar
  14. 14.
    Govindan S, McElligott A, Muthusamy S, Nair N, Barefield D, Martin JL, Gongora E, Greis KD, Luther PK, Winegrad S, Henderson KK, Sadayappan S (2012) Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction. J Mol Cell Cardiol 52:154–164CrossRefPubMedGoogle Scholar
  15. 15.
    Grimes KM, Lindsey ML, Gelfond JA, Buffenstein R (2012) Getting to the heart of the matter: age-related changes in diastolic heart function in the longest-lived rodent, the naked mole rat. J Gerontol A Biol Sci Med Sci 67:384–394CrossRefPubMedGoogle Scholar
  16. 16.
    Grimes KM, Reddy AK, Lindsey ML, Buffenstein R (2014) And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat. Am J Physiol Heart Circ Physiol 307:H284–H291CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Grimes KM, Voorhees A, Chiao YA, Han HC, Lindsey ML, Buffenstein R (2014) Cardiac function of the naked mole-rat: ecophysiological responses to working underground. Am J Physiol Heart Circ Physiol 306:H730–H737CrossRefPubMedGoogle Scholar
  18. 18.
    Hamilton N, Ianuzzo CD (1991) Contractile and calcium regulating capacities of myocardia of different sized mammals scale with resting heart rate. Mol Cell Biochem 106:133–141CrossRefPubMedGoogle Scholar
  19. 19.
    Hunkeler NM, Kullman J, Murphy AM (1991) Troponin I isoform expression in human heart. Circ Res 69:1409–1414CrossRefPubMedGoogle Scholar
  20. 20.
    Kampourakis T, Sun YB, Irving M (2016) Myosin light chain phosphorylation enhances contraction of heart muscle via structural changes in both thick and thin filaments. Proc Natl Acad Sci U S A 113:E3039–E3047CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Katrukha IA, Gusev NB (2013) Enigmas of cardiac troponin T phosphorylation. J Mol Cell Cardiol 65:156–158CrossRefPubMedGoogle Scholar
  22. 22.
    Keane M, Craig T, Alfoldi J, Berlin AM, Johnson J, Seluanov A, Gorbunova V, Di Palma F, Lindblad-Toh K, Church GM, de Magalhaes JP (2014) The naked mole rat genome resource: facilitating analyses of cancer and longevity-related adaptations. Bioinformatics 30:3558–3560CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Konishi M, Akiyama E, Iwahashi N, Maejima N, Tsukahara K, Hibi K, Kosuge M, Ebina T, Kimura K (2015) Hypercapnia in patients with acute heart failure. Eur Heart J 36:155–155Google Scholar
  24. 24.
    Korte FS, McDonald KS (2007) Sarcomere length dependence of rat skinned cardiac myocyte mechanical properties: dependence on myosin heavy chain. J Physiol 581:725–739CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Layland J, Solaro RJ, Shah AM (2005) Regulation of cardiac contractile function by troponin I phosphorylation. Cardiovasc Res 66:12–21CrossRefPubMedGoogle Scholar
  26. 26.
    Lewis KN, Soifer I, Melamud E, Roy M, McIsaac RS, Hibbs M, Buffenstein R (2016) Unraveling the message: insights into comparative genomics of the naked mole-rat. Mamm Genome 27:259–278CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, Buffenstein R (2015) Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proc Natl Acad Sci U S A 112:3722–3727PubMedPubMedCentralGoogle Scholar
  28. 28.
    Liang S, Mele J, Wu Y, Buffenstein R, Hornsby PJ (2010) Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9:626–635CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Locher MR, Razumova MV, Stelzer JE, Norman HS, Moss RL (2011) Effects of low-level α-myosin heavy chain expression on contractile kinetics in porcine myocardium. Am J Physiol Heart Circ Physiol 300:H869–H878CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lovegrove BG (1989) The cost of burrowing by the social mole rats (Bathyergidae) Cryptomys damarensis and Heterocephalus glaber: the role of soil moisture. Physiol Zool 62:449–469CrossRefGoogle Scholar
  31. 31.
    Maina JN, Maloiy GMO, Makanya AN (1992) Morphology and Morphometry of the lungs of 2 east-African mole rats, Tachyoryctes-Splendens and Heterocephalus-Glaber (Mammalia, Rodentia). Zoomorphology 112:167–179CrossRefGoogle Scholar
  32. 32.
    Marston SB, de Tombe PP (2008) Troponin phosphorylation and myofilament Ca2+−sensitivity in heart failure: increased or decreased? J Mol Cell Cardiol 45:603–607CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Narolska NA, van Loon RB, Boontje NM, Zaremba R, Penas SE, Russell J, Spiegelenberg SR, Huybregts MA, Visser FC, de Jong JW, van der Velden J, Stienen GJ (2005) Myocardial contraction is 5-fold more economical in ventricular than in atrial human tissue. Cardiovasc Res 65:221–229CrossRefPubMedGoogle Scholar
  34. 34.
    Park TJ, Reznick J, Peterson BL, Blass G, Omerbasic D, Bennett NC, Kuich PHJL, Zasada C, Browe BM, Hamann W, Applegate DT, Radke MH, Kosten T, Lutermann H, Gavaghan V, Eigenbrod O, Begay V, Amoroso VG, Govind V, Minshall RD, Smith ESJ, Larson J, Gotthardt M, Kempa S, Lewin GR (2017) Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356:305–308CrossRefGoogle Scholar
  35. 35.
    Penz OK, Fuzik J, Kurek AB, Romanov R, Larson J, Park TJ, Harkany T, Keimpema E (2015) Protracted brain development in a rodent model of extreme longevity. Sci Rep 5:11592CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Peterson BL, Larson J, Buffenstein R, Park TJ, Fall CP (2012) Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus. PLoS One 7:e31568CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Peterson BL, Park TJ, Larson J (2012) Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals. Neurosci Lett 506:342–345CrossRefPubMedGoogle Scholar
  38. 38.
    Pope B, Hoh JF, Weeds A (1980) The ATPase activities of rat cardiac myosin isoenzymes. FEBS Lett 118:205–208CrossRefPubMedGoogle Scholar
  39. 39.
    Pound KM, Arteaga GM, Fasano M, Wilder T, Fischer SK, Warren CM, Wende AR, Farjah M, Abel ED, Solaro RJ, Lewandowski ED (2011) Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia. J Mol Cell Cardiol 51:236–243CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Prothero J, Jurgens K (1987) Scaling of maximal life span in mammals: a review. In: Woodhead A, Thompson K (eds) Evolution of longevity in animals: a comparative approach. Plenum Press, New York, pp 49–74CrossRefGoogle Scholar
  41. 41.
    Puglisi JL, Goldspink PH, Gomes AV, Utter MS, Bers DM, Solaro RJ (2014) Influence of a constitutive increase in myofilament Ca(2+)-sensitivity on Ca(2+)-fluxes and contraction of mouse heart ventricular myocytes. Arch Biochem Biophys 552-553:50–59CrossRefPubMedGoogle Scholar
  42. 42.
    Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H (2007) Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12:331–343CrossRefPubMedGoogle Scholar
  43. 43.
    Razeghi P, Essop MF, Huss JM, Abbasi S, Manga N, Taegtmeyer H (2003) Hypoxia-induced switches of myosin heavy chain iso-gene expression in rat heart. Biochem Biophys Res Commun 303:1024–1027CrossRefPubMedGoogle Scholar
  44. 44.
    Reiser PJ, Kline WO (1998) Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species. Am J Phys 274:H1048–H1053Google Scholar
  45. 45.
    Sabbah HN, Sharov VG, Goldstein S (2000) Cell death, tissue hypoxia and the progression of heart failure. Heart Fail Rev 5:131–138CrossRefPubMedGoogle Scholar
  46. 46.
    Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW 2nd, Klevitsky R, Seidman CE, Seidman JG, Robbins J (2005) Cardiac myosin-binding protein-C phosphorylation and cardiac function. Circ Res 97:1156–1163CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Scruggs SB, Reisdorph R, Armstrong ML, Warren CM, Reisdorph N, Solaro RJ, Buttrick PM (2010) A novel, in-solution separation of endogenous cardiac sarcomeric proteins and identification of distinct charged variants of regulatory light chain. Mol Cell Proteomics 9:1804–1818CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Scruggs SB, Solaro RJ (2011) The significance of regulatory light chain phosphorylation in cardiac physiology. Arch Biochem Biophys 510:129–134CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Streng AS, de Boer D, van der Velden J, van Dieijen-Visser MP, Wodzig WK (2013) Posttranslational modifications of cardiac troponin T: an overview. J Mol Cell Cardiol 63:47–56CrossRefPubMedGoogle Scholar
  50. 50.
    Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, Seluanov A (2013) High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499:346–349CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Triplett JC, Swomley A, Kirk J, Lewis K, Orr M, Rodriguez K, Cai J, Klein JB, Buffenstein R, Butterfield DA (2015) Metabolic clues to salubrious longevity in the brain of the longest-lived rodent: the naked mole-rat. J Neurochem 134:538–550CrossRefPubMedGoogle Scholar
  52. 52.
    Urboniene D, Dias FA, Pena JR, Walker LA, Solaro RJ, Wolska BM (2005) Expression of slow skeletal troponin I in adult mouse heart helps to maintain the left ventricular systolic function during respiratory hypercapnia. Circ Res 97:70–77CrossRefPubMedGoogle Scholar
  53. 53.
    van der Velden J, Moorman AFM, Stienen GJM (1998) Age-dependent changes in myosin composition correlate with enhanced economy of contraction in guinea-pig hearts. J Physiol-London 507:497–510CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wang L, Muthu P, Szczesna-Cordary D, Kawai M (2013) Characterizations of myosin essential light chain's N-terminal truncation mutant Delta43 in transgenic mouse papillary muscles by using tension transients in response to sinusoidal length alterations. J Muscle Res Cell Motil 34:93–105CrossRefPubMedGoogle Scholar
  55. 55.
    Wolska BM, Vijayan K, Arteaga GM, Konhilas JP, Phillips RM, Kim R, Naya T, Leiden JM, Martin AF, de Tombe PP, Solaro RJ (2001) Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions. J Physiol 536:863–870CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Kelly M. Grimes
    • 1
    • 2
  • David Y. Barefield
    • 3
    • 4
  • Mohit Kumar
    • 3
    • 5
  • James W. McNamara
    • 5
  • Susan T. Weintraub
    • 6
  • Pieter P. de Tombe
    • 3
  • Sakthivel Sadayappan
    • 3
    • 5
  • Rochelle Buffenstein
    • 1
    • 2
    • 7
    Email author
  1. 1.Department of PhysiologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  2. 2.Sam and Ann Barshop Institute for Aging and Longevity StudiesUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  3. 3.Department of Cell and Molecular Physiology, Health Sciences DivisionLoyola University ChicagoMaywoodUSA
  4. 4.Center for Genetic MedicineNorthwestern UniversityChicagoUSA
  5. 5.Heart, Lung and Vascular InstituteUniversity of CincinnatiCincinnatiUSA
  6. 6.Department of BiochemistryUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  7. 7.Calico Life SciencesSouth San FranciscoUSA

Personalised recommendations