The role of CaMKII in diabetic heart dysfunction


Diabetes mellitus (DM) is an increasing epidemic that places a significant burden on health services worldwide. The incidence of heart failure (HF) is significantly higher in diabetic patients compared to non-diabetic patients. One underlying mechanism proposed for the link between DM and HF is activation of calmodulin-dependent protein kinase (CaMKIIδ). CaMKIIδ mediates ion channel function and Ca2+ handling during excitation–contraction and excitation-transcription coupling in the myocardium. CaMKIIδ activity is up-regulated in the myocardium of diabetic patients and mouse models of diabetes, where it promotes pathological signaling that includes hypertrophy, fibrosis and apoptosis. Pharmacological inhibition and knockout models of CaMKIIδ have shown some promise of a potential therapeutic benefit of CaMKIIδ inhibition, with protection against cardiac hypertrophy and apoptosis reported. This review will highlight the pathological role of CaMKIIδ in diabetes and discuss CaMKIIδ as a therapeutic target in DM, and also the effects of exercise on CaMKIIδ.

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  1. 1.

    Whiting DR, Guariguata L, Weil C, Shaw J (2011) IDF diabetes atlas: global estimate of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321

  2. 2.

    Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149

  3. 3.

    Kannel WB, McGee DL (1979) Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 2:120–126

  4. 4.

    Marwick TH (2006) Diabetic heart disease. Heart 92:296–300

  5. 5.

    Hayat SA, Patel B, Khattar RS, Malik RA (2004) Diabetic cardiomyopathy: mechanisms, diagnosis and treatment. Clin Sci 107:539–557

  6. 6.

    Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30:595–602

  7. 7.

    Malmberg K, Ryden L (1987) Myocardial infarction in patients with diabetes mellitus. Eur Heart J 9:259–264

  8. 8.

    Adeghate E (2004) Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem 18:1–5

  9. 9.

    Simone G, Devereux RB, Howard BV (2010) Diabetes and incident heart failure in hypertensive and normotensive participants of the strong heart study. J Hypertens 28:353–360

  10. 10.

    Asmal AC, Leary WP, Thandroyen F (1980) Diabetic heart disease. S Afr Med J 57:788–790

  11. 11.

    Rawal S, Manning P, Katare R (2014) Cardiovascular microRNAs: as modulators and diagnostic biomarkers of diabetic heart disease. Cardiovasc Diabetol 13:1–24

  12. 12.

    Bugger H, Abel ED (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57:660–671

  13. 13.

    Hasenfuss G (1997) Calcium handling proteins in the failing human heart. Basic Res Cardiol 92:87–93

  14. 14.

    Hasenfuss G (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37:279–289

  15. 15.

    Hasenfuss G, Pieske B (2002) Calcium cycling in congestive heart failure. JMCC 34:951–969

  16. 16.

    Bers DM (2006) Altered cardiac myocyte Ca2+ regulation in heart failure. Physiology 21:380–387

  17. 17.

    Ather S, Rrespress JL, Li Na L, Wehrens XHT (2013) Alterations in ryanodine receptors and related proteins in heart failure. Biochim Biophys Acta 1832:2425–2431

  18. 18.

    Luo M, Anderson ME (2013) Mechanisms of altered Ca2+ handling in heart failure. Circ Res 113:690–708

  19. 19.

    Fabiato A, Fabiato F (1979) Calcium and cardiac excitation-contraction coupling. Ann Rev Physiol 41:473–484

  20. 20.

    Bers DM (2008) Excitation-contraction coupling and cardiac contractile force. In: Excitation contraction coupling and cardiac contractile force, 2nd edn. Springer, Netherlands, pp 203–244

  21. 21.

    Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205

  22. 22.

    Fabiato A (1983) Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245:1–14

  23. 23.

    Stern MD, Capogrossi MC, Lakatta EG (1988) Spontaneous calcium release from the sarcoplasmic reticulum in myocardial cells: mechanisms and consequences. Cell Calcium 9:247–256

  24. 24.

    Lukyanenko V, Gyorke I, Gyorke S (1996) Regulation of calcium release by calcium inside the sarcoplasmic reticulum in ventricular myocytes. Eur J Physiol 432:1047–1054

  25. 25.

    Solaro RJ, Rarick HM (1998) Troponin and tropomyosin proteins that switch on and tune in the activity of cardiac myofilaments. Circ Res 83:471–480

  26. 26.

    Bers DM (2000) Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 87:275–281

  27. 27.

    Zhang X, Chen C (2012) A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine 41:398–409

  28. 28.

    Lopaschuk GD, Tahiliani AG, Vadlamudi RV, Katz S, McNeill JH (1983) Cardiac sarcoplasmic reticulum function in insulin-or carnitine-treated diabetic rats. Am J Physiol Heart Circ Physiol 245:969–976

  29. 29.

    Flarsheim CE, Grupp IL, Matlib MA (1996) Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart. Am J Physiol Heart Circ Physiol 271:192–202

  30. 30.

    Ye G, Metreveli NS, Ren J, Epstein PN (2003) Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52:777–783

  31. 31.

    Ye G, Metreveli NS, Donthi RV, Xia S, Xu M, Carlson EC, Epstein PN (2004) Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 53:1336–1343

  32. 32.

    Kralik PM, Ye G, Metreveli NS, Shem X, Epstein PN (2005) Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes. Cardiovasc Toxicol 5:285–292

  33. 33.

    Bugger H, Abel ED (2009) Rodent models of diabetic cardiomyopathy. Dis Model Mech 2:454–466

  34. 34.

    Belke DD, Swanson EA, Dillmann WH (2004) Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53:3201–3208

  35. 35.

    Pereira L, Matthes J, Schuster I, Valdiva HH, Herzig S, Richard S, Gomez AM (2006) Mechanisms of [Ca2+] transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes 55:608–615

  36. 36.

    Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ, Skapura DG et al (2009) Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J Clin Invest 119:1940–1951

  37. 37.

    Fischer TH, Herting J, Tirilomis T, Renner A, Neef S, Toischer K et al (2013) CaMKII and PKA differentially regulate SR Ca2=- leak in human cardiac pathology. Circ 128:970–981

  38. 38.

    Fischer TH, Eiringhaus J, Dybkova N, Forster A, Herting J, Kleinwachter A et al (2014) Ca(2+)/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca(2+) leak in human ischaemic dilated cardiomyopathy. Eur J Heart Fail 16:1292–1300

  39. 39.

    Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N, Neumann K et al (2010) CaMKII dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res 106:1134–1144

  40. 40.

    Maier LS, Zhang T, Chen L, DeSantiago J, Brown JH, Bers DM (2003) Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release. Circ Res 92:904–911

  41. 41.

    Maier LS, Bers DM (2002) Calcium, calmodulin and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Moll Cell Cardiol 34:919–939

  42. 42.

    Zhang T, Brown JH (2004) Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. Cardiovas Res 63:476–486

  43. 43.

    Braun AP, Schulman H (2005) The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu Rev Physiol 57:417–445

  44. 44.

    Lin CR, Kapiloff MS, Durgerian S, Tatemoto K, Russo AF, Hanson P et al (1987) Molecular cloning of a brain-specific calcium-calmodulin-dependent protein kinase. Proc Natl Acad Sci USA 84:5962–5966

  45. 45.

    Kelly PT, Weinburger RP, Waxham MN (1988) Active site-directed inhibition of Ca2+/calmodulin-dependent protein kinase type II by a bifunctional calmodulin-binding peptide. Proc Natl Acad Sci USA 85:4991–4995

  46. 46.

    Colbran RJ, Fong YL, Schworer CM, Soderling TR (1988) Regulatory interactions of the calmodulin-binding, inhibitory and autophosphorylation domains of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 263:18145–18151

  47. 47.

    Smith MK, Colbran RJ, Bricky DA, Soderling TR (1992) Functional determinants in the autoinhibitory domain of calcium/calmodulin-dependent protein kinase II. Role of His282 and multiple basic residues. J Biol Chem 267:1761–1768

  48. 48.

    Lou LL, Lloyd SJ, Schulman H (1986) Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase by autophosphorylation: ATP modulates production of an autonomous enzyme. Proc Natl Acad Sci USA 83:9497–9501

  49. 49.

    Meyer T, Hanson PI, Stryer L, Schulman H (1992) Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science 256:1199–1201

  50. 50.

    De Koninck P, Schulman H (1998) Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279:227–230

  51. 51.

    Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV et al (2008) A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133:462–474

  52. 52.

    Erickson JR, He JB, Grumbach IM, Anderson ME (2011) CaMKII in the cardiovascular system: sensing redox states. Physiol Rev 91:889–915

  53. 53.

    Zhang DM, Chai Y, Erickson JR, Brown JH, Bers DM, Lin YF (2014) Intracellular signaling mechanism responsible for modulation of sarcolemmal ATP-sensitive potassium channels by nitric oxide in ventricular cardiomyocytes. J Physiol 592:971–990

  54. 54.

    Coultrap SJ, Bayer KU (2014) Nitric oxide induces Ca2+ independent activity of the Ca2+/calmodulin- dependent protein kinase II (CaMKII). J Biol Chem 28:19458–19465

  55. 55.

    Hudman A, Schulman H (2002) Neuronal Ca2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Ann Rev Biochem 71:473–510

  56. 56.

    Erickson JR (2014) Mechanisms of CaMKII activation in the heart. Frontiers in Pharm Res 59:1–5

  57. 57.

    Torres CR, Hart GW (1984) Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem 259:3308–3317

  58. 58.

    Zachara NE, Hart GW (2004) O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochem Biophys Acta 1673:13–28

  59. 59.

    Zachara NE, Hart GW (2006) Cell signaling, the essential role of O-GlcNAc! Biochem Biophys Acta 1761:599–617

  60. 60.

    Hart GW (1997) Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem 66:315–335

  61. 61.

    Wells L, Whalen SA, Hart GW (2003) A regulatory post-translational modification. Biochem Biophys Res Commun 302:435–441

  62. 62.

    Comer FI, Hart GW (1999) O-GlcNAc and the control of gene expression. Biochem Biophys Acta 1473:161–171

  63. 63.

    McLarty JL, Marsh SA, Chatham JC (2013) Post-translational protein modification by O-linked N-acetyl-glucosamine: its role in mediating the adverse effects of diabetes on the heart. Life Sci 92:621–627

  64. 64.

    Chatham JC, Marchase RB (2010) The role of protein O-linked B-N-acetylglucosamine in mediating cardiac stress response. Biochem Biophys Acta 1800:57–66

  65. 65.

    Medford HM, Chatham JC, Marsh SA (2012) Chronic ingestion of a western diet increases O-linked-B-N-acetylglucosamine (O-GlcNAc) protein modification in the rat heart. Life Sci 90:23–24

  66. 66.

    Taylor RP, Parker GJ, Hazel MW, Soesanto Y, Fuller W, Yazzie MJ et al (2008) Glucose deprivation stimulates O-GlcNAC modification of proteins through upregulation of O-linked N-acetylglucosaminyltransferase. J Biol Chem 283:6050–6057

  67. 67.

    Zou L, Zhu-Maldin Z, Marchase RB, Paterson AJ, Liu J, Yang Q, Chatham JC (2012) Glucose deprivation-induced increase in protein O-GlcNAcylation in cardiomyocytes is calcium dependent. J Biol Chem 287:34419–34431

  68. 68.

    Hu Y, Belke D, Suarez J, Swanson E, Clark R, Hoshijima M et al (2005) Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ Res 96:1006–1013

  69. 69.

    Yokoe S, Ashai M, Takeda T, Otsu K, Taniguchi N, Miyoshi E et al (2010) Inhibition of phospholamban phosphorylation by O-GlcNAcylation: implications for diabetic cardiomyopathy. Glycobio 20:1217–1226

  70. 70.

    Erickson JR, Pereira L, Wang L, Han G, Ferguson A, Dao K et al (2013) Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycolysation. Nature 502:372–376

  71. 71.

    Liu J, Marchase RB, Chatham JC (2007) Glutamine-induced protection of isolated rat heart from ischemia/reperfusion injury is mediated via the hexosamine biosynthesis pathway and increase protein O-GlcNAc levels. JMCC 42:177–185

  72. 72.

    Zachara NE, O’Donnell N, Cheng WD, Mercer JJ, Marth JD, Hart GW (2004) Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress: a survival response in mammalian cells. J Biol Chem 279:30133–30142

  73. 73.

    Zou L, Yang S, Hu S, Chaudry IH, Marchase RB, Chatham JC (2007) The protective effects of PUGNAc on cardiac function after trauma-hemorrhage are mediated via increase protein O-GlcNAc levels. Shock 27:402–408

  74. 74.

    Zou L, Yang S, Champattanachai V, Hu S, ChauDRY IH, Marchase RB et al (2009) Glucosamine improves cardiac function following trauma-hemorrhage by increase protein O-GlcNAcylation and attenuation of NF-(kappa) b signaling. Am J Physiol Heart Circ Physiol 296:515–523

  75. 75.

    Anderson ME, Brown JH, Bers DM (2011) CaMKII in myocardial hypertrophy and heart failure. J Mol Cell Cardiol 51:468–473

  76. 76.

    Swaminathan PD, Purohit A, Hund TJ, Anderson ME (2012) Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias. Circ Res 110:1661–1677

  77. 77.

    Couchonnal LF, Anderson ME (2008) The role of calmodulin kinase II in myocardial physiology and disease. Physiology 23:151–159

  78. 78.

    Witcher DR, Kovacs RJ, Schulman H, Cefali DC, Jones LR (1991) Unique phosphorylation site on the cardiac ryanodine receptor regulates calcium channel activity. J Biol Chem 266:11144–11152

  79. 79.

    Wehrens XH, Lehnart SE, Reiken SR, Marks AR (2004) Ca2+/calmodulin dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ Res 94:61–70

  80. 80.

    Simmerman HK, Collins JH, Theibert JL, Wegener AD, Jones LR (1986) Sequence analysis of phospholamban. Identification of phosphorylation sites and two major structural domains. J Biol Chem 261:13333–13341

  81. 81.

    Brittsan AG, Kranias EG (2000) Phospholamban and cardiac contractile function. J Mol Cell Card 32:2131–2139

  82. 82.

    Hook SS, Means AR (2001) Ca2+/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol 41:471–505

  83. 83.

    Kirchhefer U, Schmitz W, Scholz H, Neumann J (1999) Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts. Cardiovas Res 42:254–261

  84. 84.

    Hoch B, Meyer R, Hetzer R, Krause EG, Karczewski P (1999) Identification and expression of δ isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. Circ Res 84:713–721

  85. 85.

    Sossalla S, Fluschnik N, Schotola H, Ort KR, Neef S, Schulte T et al (2010) Inhibition of elevated Ca2+/calmdoulin-dependent protein kinase II improves contractility in human failing myocardium. Circ Res 107:1150–1161

  86. 86.

    Zhang T, Maier LS, Dalton ND, Miyamoto S, Ross J, Donald M et al (2003) The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ Res 92:912–919

  87. 87.

    Reuter H, Gronke S, Adam C, Ribati M, Brabender J, Zobel C et al (2008) Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients. Mol Cell Biochem 308:141–149

  88. 88.

    Lamberts RR, Lingam SJ, Wang H, Bollen IAE, Hughes G, Galvin IF et al (2014) Impaired relaxation despite upregulated calcium-handling pro in atrial myocardium from type 2 diabetic patients with preserved ejection fraction. Cardiovasr diabetol 13:72

  89. 89.

    Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9

  90. 90.

    Jay D, Hitomi H, Griendling KK (2006) Oxidative stress and diabetic cardiovascular complications. Free Rad Bio Med 40:183–192

  91. 91.

    Luo M, Guan X, Luczak ED, Lang D, Kutschke W, Gao Z et al (2013) Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest 123:1262–1274

  92. 92.

    Purohit A, Rokita AG, Guan X, Chen B, Koval OM, Voigt N et al (2013) Oxidized CaMKII triggers atrial fibrillation. Circulation 128:1748–1757

  93. 93.

    Song Y, Shryock JC, Belardinelli L (2008) An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes. Am J Physiol Heart Circ Physiol 294:2031–2039

  94. 94.

    Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV, Glukhov AV et al (2011) Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest 121:3277–3288

  95. 95.

    Voigt N, Li N, Wang Q, Wang W, Trafford AW, Abu-Taha I et al (2012) Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+–Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circ 125:2059–2070

  96. 96.

    Weiss JN, Garfinkel A, Karaguezian HS, Chen P, Qu Z (2010) Early afterdepolarizations and cardiac arrhythmias. Heart rhythm 7:1891–1899

  97. 97.

    Westenbrink BD, Edwards AG, McCulloch AD, Brown JH (2013) The promise of CaMKII inhibition for heart disease: preventing heart failure and arrhythmias. Expert Opin Ther Targets 17:889–903

  98. 98.

    Luczak ED, Anderson ME (2014) CaMKII oxidative activation and the pathogenesis of cardiac disease. JMCC 73:112–116

  99. 99.

    Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towhin J, Vincent GM (1996) Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps and future directions. The SADS foundation task force on LQTS. Circ 94:1996–2012

  100. 100.

    Anderson ME, Braun AP, Wu Y, Lu T, Wu Y, Schulman H, Sung RJ (1998) KN-93 an inhibitor of multifunctional Ca++/calmodulin-depenent protein kinase, decreases early afterdepolarization in rabbit heart. J Pharm Exp Tech 287:996–1006

  101. 101.

    Venetucci LA, Trafford AW, O’Neill SC, Eisner DA (2008) The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovas Res 77:285–292

  102. 102.

    Wright SC, Schellenberger U, Ji L, Wang H, Larrick JW (1997) Calmodulin-dependent protein kinase II mediates signal transduction in apoptosis. FASEBJ 11:843–849

  103. 103.

    Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M et al (2003) The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca2+ pathway to antagonize Wnt/B-catening signaling. Mol Cell Bio 23:131–139

  104. 104.

    Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S, Ninomiya-Tsjui J et al (2004) Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep 5:161–166

  105. 105.

    Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T et al (1994) JNKI: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037

  106. 106.

    Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogen 27:6245–6251

  107. 107.

    Zhu W, Woo AY, Yang D, Cheng H, Crow MT, Xiao R (2007) Activation of CaMKIIdeltaC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis. J Biol Chem 282:10833–10839

  108. 108.

    Chen X, Zhang X, Kubo H, Harris DM, Mills GD, Moyer J et al (2005) Ca2+ influx induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. Circ Res 97:1009–1017

  109. 109.

    Joiner MA, Koval OM, Jingdong Li, He JB, Allamargot C, Gao Z et al (2012) CaMKII determines mitochondrial stress responses in heart. Nature 491:269–273

  110. 110.

    Maisch B, Alter P, Pankuweit S (2011) Diabetic cardiomyopathy-fact or fiction? Herz 36:102–115

  111. 111.

    Cai L, Kang YJ (2001) Oxidative stress and cardiomyopathy: a brief review. Cardiovasc Toxicol 1:181–193

  112. 112.

    Ren J, Gintant GA, Miller RE, Davidoff AJ (1994) High extracellular glucose impairs cardiac E-C coupling in a glycolysation-dependent manner. Am J Physiol 273:2876–2883

  113. 113.

    Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M et al (2003) Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278:44230–44237

  114. 114.

    Cai L, Li Wei, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium- mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetes 51:1938–1948

  115. 115.

    Backlund T, Palojoki E, Saraste A, Eriksson A, Finckenberg P, Kyto V et al (2004) Sustained cardiomyocytes apoptosis and left ventricular remodeling after myocardial infarction in experimental diabetes. Diabetologia 47:325–330

  116. 116.

    Zhang R, Kooh MSC, Wu Y, Yang Y, Grueter CE, Ni G et al (2005) Calmodulin kinase II inhibition protects against structural heart disease. Nat Med 11:409–417

  117. 117.

    Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick DM et al (2009) The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc Natl Acad Sci USA 106:2342–2347

  118. 118.

    Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y et al (2009) Requirement for Ca2+/calmodulin-dependent kinase II in the transition from the pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest 119:1230–1240

  119. 119.

    Cheng J, Xu L, Lai D, Guilbert A, Lim HJ, Keskanokwong T et al (2012) CaMKII inhibition in heart failure, beneficial, harmful or both. Am J Physiol 302:1453–1465

  120. 120.

    Maier LS, Bers DM (2007) Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. Cardiovas Res 73:631–640

  121. 121.

    Sumi M, Kiuchi K, Ishikawa T, Ishii A, Hagiwara M, Nagatsu T, Hidika H (1991) The newly synthesized selective Ca2+/calmodulin-dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12H cells. Biochem Biophys Res Commun 181:968–975

  122. 122.

    Ishida A, Kameshita I, Okuno S, Kitani T, Fujisawa H (1995) A novel specific and potent inhibitor of calmodulin-dependent protein kinase II. Biochem Biophys Res Commun 212:806–812

  123. 123.

    Sag CM, Wadsack DP, Khabbazzadeh S, Abesser M, Grefe C, Neumann K et al (2009) Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. Circ Heart Fail 2:664–675

  124. 124.

    Pellicena P, Schulamn H (2014) CaMKII inhibitors: from research tools to therapeutic agents. Front Pharma 5:1–10

  125. 125.

    Stolen TO, Hoydal MA, Kemi OJ, Catalucci D, Ceci M, Aasum E et al (2009) Interval training normalizes cardiomyocytes function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circ Res 105:527–536

  126. 126.

    Chudyk A, Petrella RJ (2011) Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta analysis. Diabetes Care 34:1228–1237

  127. 127.

    Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ (2001) Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta analysis of controlled trials. JAMA 286:1218–1227

  128. 128.

    Cuff DJ, Meneilly GS, Martin A, Ignaszewski A, Tidesley HD, Frohlich JJ (2003) Effective exercise modality to reduce insulin resistance in women with type 2 diabetes. Diabetes Care 26:2977–2982

  129. 129.

    Bordenave S, Brandou F, Manetta J, Fedou C, Mercier J, Brun JF (2007) Effects of acute exercise on insulin sensitivity, glucose effectiveness and disposition index in type 2 diabetic patients. Diabetes Metab 34(250):257

  130. 130.

    Brassard P, Legault S, Garneau C, Bogaty P, Dumesnil JG, Poirier P (2007) Normalization of diastolic dysfunction in type 2 diabetics after exercise training. Med Sci Sports Exerc 39:1896–1901

  131. 131.

    Lamberts S, Van Laethem C, Van Acker K, Calders P (2008) Influence of combined exercise training on indices of obesity, diabetes and cardiovascular risk in type 2 diabetes patients. Clin Rehabil 22(483):492

  132. 132.

    Malfatto G, Facchini M, Bragato R, Branzi G, Sala L, Leonetti G (1996) Short and long term effects of exercise training on the tonic autonomic modulation of heart rate variability after myocardial infarction. Eur Heart J 17:532–538

  133. 133.

    Oldrige NB, Guyatt GG, Fischer ME, Rimm AA (1988) Cardiac rehabilitation after myocardial infarction: combined experience of randomized clinical trials. J Am Med Assoc 260:945–950

  134. 134.

    Philip A, Ades MD (2001) Cardiac rehabilitation and secondary prevention of coronary heart disease. N Engl J Med 345:892–902

  135. 135.

    Taylor RS, Brown A, Ebrahim S, Joliffe J, Noorani H, Rees K et al (2003) Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 116:682–692

  136. 136.

    Banzer JA, Maguire TE, Kennedy CM, O’Malley CJ, Balady GJ (2004) Results of cardiac rehabilitation in patients with diabetes mellitus. Am J Cardiol 93:81–84

  137. 137.

    Boukhris M, Tomasello D, Khanfir R, Elhadj Z, Terra AW, Marza F et al (2015) Impact of cardiac rehabilitation on ventricular repolarization indexes and ventricular arrhythmias in patients affected by coronary artery disease and type 2 diabetes. Heart Lung 44:199–204

  138. 138.

    Horden MD, Dunstan DW, Prins JB, Baker MK, Fiatarone Singh MA, Coombes JS (2012) Exercise prescription for patients with type 2 diabetes and pre-diabetes: a position statement from exercise and sport science Australia. J Sci Med Spor 15:25–31

  139. 139.

    Boule NG, Kenny GP, Haddad E, Wells GA, Sigal RJ (2003) Meta-analysis of the effect of structured exercise training on cardiorespiratory fitness in type 2 diabetes mellitus. Diabetologia 46:1071–1081

  140. 140.

    Gibala MJ, Little JP, van Essen M, Wilkin GP, Burgomaster KA, Safdar A et al (2006) Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance. J Physiol 575:901–911

  141. 141.

    Hood MS, Little JP, Tarnopolsky MA, Myslik F, Gibala MJ (2011) Low-volume interval training improves muscle oxidative capacity in sedentary adults. Med Sci Sports Exerc 43:1849–1856

  142. 142.

    Little JP, Safdar A, Wilkin GO, Tarnopolsky MA, Gibala MJ (2010) A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. J Physiol 588:1011–1022

  143. 143.

    Bloomgarden ZT (1999) American Diabetes Association annual meeting—diabetes and obesity. Diabetes Care 23:118–124

  144. 144.

    Linke SE, Gallo LC, Norman GJ (2011) Attrition and adherence rates of sustained vs. intermittent exercise interventions. Ann Behav Med 42:197–209

  145. 145.

    Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F (2004) Strength training increases insulin-mediated uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes 53:294–305

  146. 146.

    Yang Z, Scott CA, Mao C, Tang J, Farmer AJ (2013) Resistance exercise versus aerobic exercise for type 2 diabetes: a systematic review and meta-analysis. Sports Med 44:487–499

  147. 147.

    Sigal RJ, Kenny GP, Boule NG, Wells GA, Prud’homme D, Fortier M et al (2007) Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 147:357–369

  148. 148.

    Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K et al (2010) Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA 304:2253–2262

  149. 149.

    Kemi OJ, Ellingsen O, Ceci M, Grimaldi S, Smith GL, Condorelli G et al (2007) Aerobic interval training enhances cardiomyocytes contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban. J Mol Cell Cardiol 43:354–361

  150. 150.

    Kaurstad G, Alves MN, Kemi OJ, Rolim N, Hoydal MA, Wisloff H et al (2012) Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training. Eur J App Physiol 112:579–588

  151. 151.

    Bennett CE, Virginia L, Shearer J, Belke DD (2013) Exercise training mitigates aberrant cardiac protein O-GlcNAcylation in streptozotocin-induced diabetic mice. Life Sci 92:657–663

  152. 152.

    Belke DD (2011) Swim-exercised mice show a decreased level of protein O-GlcNAcylation and expression of O-GlcNAc transferase in the heart. J App Physiol 111:157–162

  153. 153.

    Cox EJ, Marsh SA (2013) Exercise and diabetes have opposite effects on the assembly and O-GlcNAc modification of the mSin3A/HDAC1/2 complex in the heart. Cardiovas Diabetol 12:101

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This publication was written with support from the Marsden Fund of the Royal Society of New Zealand (13-UOO-193) for J.R.E. and a University of Otago Department of Physiology scholarship for L.D.

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Correspondence to Jeffrey R. Erickson.

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Daniels, L., Bell, J.R., Delbridge, L.M.D. et al. The role of CaMKII in diabetic heart dysfunction. Heart Fail Rev 20, 589–600 (2015).

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  • CaMKII
  • Diabetes mellitus
  • Diabetic heart dysfunction
  • Heart failure
  • Exercise