title: Inhibition of plasminogen activator inhibitor-1 restores skeletal muscle regeneration in untreated type 1 diabetic mice.
abstract: OBJECTIVE
  Type 1 diabetes leads to impairments in growth, function, and regenerative capacity of skeletal muscle; however, the underlying mechanisms have not been clearly defined.
  
  
  METHODS
  With the use of Ins2(WT/C96Y) mice (model of adolescent-onset type 1 diabetes), muscle regeneration was characterized in terms of muscle mass, myofiber size (cross-sectional area), and protein expression. Blood plasma was analyzed for glucose, nonesterified fatty acids, insulin, and plasminogen activator inhibitor-1 (PAI-1). PAI-039, an effective inhibitor of PAI-1, was orally administered to determine if PAI-1 was attenuating muscle regeneration in Ins2(WT/C96Y) mice.
  
  
  RESULTS
  Ins2(WT/C96Y) mice exposed to 1 or 8 weeks of untreated type 1 diabetes before chemically induced muscle injury display significant impairments in their regenerative capacity as demonstrated by decreased muscle mass, myofiber cross-sectional area, myogenin, and Myh3 expression. PAI-1, a physiologic inhibitor of the fibrinolytic system and primary contributor to other diabetes complications, was more than twofold increased within 2 weeks of diabetes onset and remained elevated throughout the experimental period. Consistent with increased circulating PAI-1, regenerating muscles of diabetic mice exhibited excessive collagen levels at 5 and 10 days postinjury with concomitant decreases in active urokinase plasminogen activator and matrix metalloproteinase-9. Pharmacologic inhibition of PAI-1 with orally administered PAI-039 rescued the early regenerative impairments in noninsulin-treated Ins2(WT/C96Y) mice.
  
  
  CONCLUSIONS
  Taken together, these data illustrate that the pharmacologic inhibition of elevated PAI-1 restores the early impairments in skeletal muscle repair observed in type 1 diabetes and suggests that early interventional studies targeting PAI-1 may be warranted to ensure optimal growth and repair in adolescent diabetic skeletal muscle.
authors: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: Matthew P
authors: MP
authors: Krause
authors: Jasmin
authors: J
authors: Moradi
authors: Aliyah A
authors: AA
authors: Nissar
authors: Michael C
authors: MC
authors: Riddell
authors: Thomas J
authors: TJ
authors: Hawke
references: Diabetes. 1997 Aug;46(8):1336-40
references: 9231659
references: Diabetes Care. 1989 Oct;12(9):655-8
references: 2507266
references: Pediatr Diabetes. 2011 Jun;12(4 Pt 1):345-64
references: 20860561
references: J Appl Physiol (1985). 2009 May;106(5):1650-9
references: 19246652
references: Blood. 2001 Mar 15;97(6):1703-11
references: 11238111
references: Int J Dev Biol. 2008;52(2-3):307-14
references: 18311722
references: Blood. 2009 Dec 3;114(24):5052-61
references: 19812386
references: Diabetes Care. 2010 Jul;33(7):1529-35
references: 20587723
references: J Musculoskelet Neuronal Interact. 2008 Apr-Jun;8(2):188-95
references: 18622088
references: J Pediatr. 1994 Aug;125(2):177-88
references: 8040759
references: Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):365-71
references: 15576638
references: Am J Med. 2003 Dec 8;115 Suppl 8A:62S-68S
references: 14678868
references: Front Biosci. 2005 Sep 01;10:2978-85
references: 15970552
references: J Appl Physiol (1985). 1989 Nov;67(5):1827-34
references: 2600016
references: Anat Rec. 2000 Feb 1;258(2):176-85
references: 10645965
references: PLoS One. 2010 May 26;5(5):e10805
references: 22421977
references: J Clin Endocrinol Metab. 2009 Sep;94(9):3171-82
references: 19509100
references: J Clin Invest. 1995 Jun;95(6):2926-37
references: 7769135
references: Diabetologia. 1990 Jan;33(1):43-51
references: 2406180
references: Eur J Biochem. 1988 May 16;174(1):103-10
references: 3371354
references: PLoS One. 2009 Oct 06;4(10):e7293
references: 19806198
references: Am J Physiol Cell Physiol. 2007 Nov;293(5):C1636-44
references: 17855775
references: Clin Neuropathol. 1986 Mar-Apr;5(2):73-7
references: 3708956
references: Coll Antropol. 2009 Dec;33(4):1115-9
references: 20102056
references: Curr Opin Cell Biol. 2007 Dec;19(6):628-33
references: 17996437
references: Exp Cell Res. 1986 Mar;163(1):211-20
references: 3002828
references: Biol Chem. 2002 Jan;383(1):127-36
references: 11928807
references: Am J Physiol Cell Physiol. 2005 Jul;289(1):C217-23
references: 15716324
references: Diabetologia. 2007 Jun;50(6):1315-26
references: 17415547
references: Diabetologia. 2009 Jun;52(6):1182-91
references: 19280173
references: Am J Physiol Cell Physiol. 2008 Jul;295(1):C203-12
references: 18463233
references: J Med Chem. 2004 Jul 1;47(14):3491-4
references: 15214776
references: Diabetes. 1997 May;46(5):887-94
references: 9133560
references: Anat Rec. 1991 Mar;229(3):298-304
references: 2024774
references: PLoS One. 2010 Nov 17;5(11):e14032
references: 21103335
references: Int J Radiat Oncol Biol Phys. 2009 Jul 1;74(3):942-8
references: 19480973
references: Am J Pathol. 2009 Aug;175(2):763-71
references: 19574431
references: J Appl Physiol (1985). 2000 Jan;88(1):158-64
references: 10642376
references: J Thromb Haemost. 2004 Aug;2(8):1422-8
references: 15304050
references: Dev Biol. 1999 Jan 1;205(1):158-70
references: 9882504
references: Pediatr Res. 2005 Aug;58(2):229-34
references: 16006430
references: Am J Physiol Cell Physiol. 2007 Mar;292(3):C1033-40
references: 17092995
references: J Appl Physiol (1985). 2001 Aug;91(2):534-51
references: 11457764
references: Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1687-96
references: 17911348
references: Nephron Exp Nephrol. 2006;104(1):e23-34
references: 16735799
references: Pathobiology. 2007;74(5):291-300
references: 17890896
references: Exp Clin Endocrinol Diabetes. 2001;109(3):146-50
references: 11409296
references: J Cell Physiol. 1994 May;159(2):379-85
references: 8163577
references: Kidney Int. 2005 Apr;67(4):1297-307
references: 15780082
references: Thromb Res. 2004;114(2):129-35
references: 15306155