Inhibition Of Plasminogen Activator Inhibitor-1 Restores Skeletal Muscle Regeneration In Untreated Type 1 Diabetic Mice

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 (PAT-1). PAI-039, an effective inhibitor of PAT-1, was orally administered to,determine if PAT-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 PM-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 PAT-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. Diabetes 60:1964-1972, 2011