title: Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice.
abstract: Although the cardiovascular benefits of exercise are well known, exercise induced effects and mechanisms in prevention of cardiomyopathy are less clear during obesity associated type-2 diabetes. The current study assessed the impact of moderate intensity exercise on diabetic cardiomyopathy by examining cardiac function and structure and mitochondrial function.
  
  
  
  Obese-diabetic (db/db), and lean control (db/+) mice, were subjected to a 5 week, 300 m run on a tread-mill for 5 days/week at the speeds of 10-11 m/min. Various physiological parameters were recorded and the heart function was evaluated with M-mode echocardiography. Contraction parameters and calcium transits were examined on isolated cardiomyocytes. At the molecular level: connexin 43 and 37 (Cx43 and 37) levels, mitochondrial biogenesis regulators: Mfn2 and Drp-1 levels, mitochondrial trans-membrane potential and cytochrome c leakage were assessed through western blotting immunohistochemistry and flow cytometry. Ability of exercise to reverse oxygen consumption rate (OCR), tissue ATP levels, and cardiac fibrosis were also determined.
  
  
  
  The exercise regimen was able to prevent diabetic cardiac functional deficiencies: ejection fraction (EF) and fractional shortening (FS). Improvements in contraction velocity and contraction maximum were noted with the isolated cardiomyocytes. Restoration of interstitial and micro-vessels associated Cx43 levels and improved gap junction intercellular communication (GJIC) were observed. The decline in the Mfn2/Drp-1 ratio in the db/db mice hearts was prevented after exercise. The exercise regimen further attenuated transmembrane potential decline and cytochrome c leakage. These corrections further led to improvements in OCR and tissue ATP levels and reduction in cardiac fibrosis.
  
  
  
  Moderate intensity exercise produced significant cardiovascular benefits by improving mitochondrial function through restoration of Cx43 networks and mitochondrial trans-membrane potential and prevention of excessive mitochondrial fission.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Veeranki
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Sathnur
authors.initials: S
authors.lastname: Pushpakumar
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D058065:Diabetic Cardiomyopathies / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009765:Obesity; D018384:Oxidative Stress / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D010805:Physical Conditioning, Animal; D000097006:Gap Junction alpha-4 Protein
chemical_list: D000255:Adenosine Triphosphate; D018031:Connexin 43; D017630:Connexins; D000097006:Gap Junction alpha-4 Protein
keywords: Connexin; Cytochrome c; Diabetes; Drp-1; Exercise; Fibrosis; Mfn-2; Mitochondrial-biogenesis; Obesity; Trans-membrane-potential
references.citation: Adv Cardiol. 2006;42:243-54
references.pmid: 16646595
references.citation: Can J Physiol Pharmacol. 2015 Sep;93(9):755-63
references.pmid: 26176406
references.citation: Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2106-18
references.pmid: 17122193
references.citation: Indian J Med Res. 2007 Mar;125(3):451-72
references.pmid: 17496368
references.citation: Am J Physiol Cell Physiol. 2008 Jul;295(1):C221-30
references.pmid: 18463230
references.citation: FASEB J. 2008 Aug;22(8):2862-71
references.pmid: 18417547
references.citation: Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1470-80
references.pmid: 18641279
references.citation: Int J Biochem Cell Biol. 2009 Apr;41(4):879-90
references.pmid: 18805504
references.citation: Circ Cardiovasc Imaging. 2010 Jan;3(1):24-31
references.pmid: 19846730
references.citation: Antioxid Redox Signal. 2010 Apr;12(4):537-77
references.pmid: 19650713
references.citation: Rev Endocr Metab Disord. 2010 Mar;11(1):31-9
references.pmid: 20180026
references.citation: Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3758-63
references.pmid: 20130277
references.citation: Diabetes Care. 2010 Dec;33(12):e147-67
references.pmid: 21115758
references.citation: FASEB J. 2011 Mar;25(3):1106-17
references.pmid: 21148111
references.citation: J Cardiovasc Pharmacol. 2011 Jun;57(6):630-8
references.pmid: 21150449
references.citation: Cell Metab. 2012 Feb 8;15(2):186-200
references.pmid: 22326220
references.citation: Am J Physiol Heart Circ Physiol. 2000 Feb;278(2):H412-9
references.pmid: 10666070
references.citation: Circ Res. 2000 Mar 3;86(4):386-90
references.pmid: 10700442
references.citation: Circulation. 2001 Jan 2;103(1):102-7
references.pmid: 11136693
references.citation: J Mol Cell Cardiol. 2012 May;52(5):1009-18
references.pmid: 22406429
references.citation: Br J Pharmacol. 2012 Jun;166(3):877-94
references.pmid: 22352879
references.citation: Circulation. 2002 Apr 16;105(15):1861-70
references.pmid: 11956132
references.citation: Diabetes. 2002 May;51(5):1565-71
references.pmid: 11978657
references.citation: Circ Res. 2002 Oct 4;91(7):640-7
references.pmid: 12364393
references.citation: Cell Death Differ. 2003 Jun;10(6):709-17
references.pmid: 12761579
references.citation: Acta Physiol Scand. 2003 Jun;178(2):97-106
references.pmid: 12780383
references.citation: Am J Cardiol. 2004 Apr 1;93(7):870-5
references.pmid: 15050491
references.citation: Biochem Biophys Res Commun. 2005 Apr 8;329(2):726-32
references.pmid: 15737646
references.citation: Free Radic Res. 2013 Jan;47(1):44-54
references.pmid: 23039789
references.citation: Diabetes. 2013 Jul;62(7):2287-94
references.pmid: 23493573
references.citation: FEBS Lett. 2014 Mar 3;588(5):836-44
references.pmid: 24492000
references.citation: Can J Physiol Pharmacol. 2014 Jul;92(7):583-91
references.pmid: 24905188
references.citation: Arch Iran Med. 2014 Aug;17(8):569-73
references.pmid: 25065281
references.citation: J Appl Physiol (1985). 2014 Aug 1;117(3):223-30
references.pmid: 24947024
references.citation: Circ Res. 2015 Jan 16;116(2):264-78
references.pmid: 25332205
references.citation: Biochim Biophys Acta. 2015 May;1852(5):732-41
references.pmid: 25615794
references.citation: Cardiovasc Diabetol. 2014;13:149
references.pmid: 25416469
references.citation: Cell Physiol Biochem. 2015;35(6):2159-68
references.pmid: 25896313
references.citation: Int J Cardiol. 2015;187:325-33
references.pmid: 25841124
references.citation: Am J Physiol Heart Circ Physiol. 2015 Jul 15;309(2):H325-34
references.pmid: 25980021
references.citation: Mol Biol Cell. 2015 Aug 1;26(15):2755-68
references.pmid: 26063728
references.citation: Pharmacol Ther. 2015 Sep;153:90-106
references.pmid: 26073311
references.citation: J Appl Physiol (1985). 2006 Jul;101(1):151-63
references.pmid: 16484365