| First Author | Krause MP | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 7 | Pages | 1964-72 |
| PubMed ID | 21593201 | Mgi Jnum | J:186757 |
| Mgi Id | MGI:5433011 | Doi | 10.2337/db11-0007 |
| Citation | Krause MP, et al. (2011) Inhibition of plasminogen activator inhibitor-1 restores skeletal muscle regeneration in untreated type 1 diabetic mice. Diabetes 60(7):1964-72 |
| abstractText | 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. RESEARCH DESIGN AND 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. |
