Abstract
BackgroundSystemic elevations in PAI-1 suppress the fibrinolytic pathway leading to poor collagen remodelling and delayed regeneration of tibialis anterior (TA) muscles in type-1 diabetic Akita mice. However, how impaired collagen remodelling was specifically attenuating regeneration in Akita mice remained unknown. Furthermore, given intrinsic differences between muscle groups, it was unclear if the reparative responses between muscle groups were different.Principal FindingsHere we reveal that diabetic Akita muscles display differential regenerative responses with the TA and gastrocnemius muscles exhibiting reduced regenerating myofiber area compared to wild-type mice, while soleus muscles displayed no difference between animal groups following injury. Collagen levels in TA and gastrocnemius, but not soleus, were significantly increased post-injury versus controls. At 5 days post-injury, when degenerating/necrotic regions were present in both animal groups, Akita TA and gastrocnemius muscles displayed reduced macrophage and satellite cell infiltration and poor myofiber formation. By 10 days post-injury, necrotic regions were absent in wild-type TA but persisted in Akita TA. In contrast, Akita soleus exhibited no impairment in any of these measures compared to wild-type soleus. In an effort to define how impaired collagen turnover was attenuating regeneration in Akita TA, a PAI-1 inhibitor (PAI-039) was orally administered to Akita mice following cardiotoxin injury. PAI-039 administration promoted macrophage and satellite cell infiltration into necrotic areas of the TA and gastrocnemius. Importantly, soleus muscles exhibit the highest inducible expression of MMP-9 following injury, providing a mechanism for normative collagen degradation and injury recovery in this muscle despite systemically elevated PAI-1.ConclusionsOur findings suggest the mechanism underlying how impaired collagen remodelling in type-1 diabetes results in delayed regeneration is an impairment in macrophage infiltration and satellite cell recruitment to degenerating areas; a phenomena that occurs differentially between muscle groups.
Highlights
Type 1 diabetes mellitus (T1DM) is an autoimmune disease defined by hyperglycemia and hypoinsulinemia in the absence of exogenous insulin treatment
Our findings suggest the mechanism underlying how impaired collagen remodelling in type-1 diabetes results in delayed regeneration is an impairment in macrophage infiltration and satellite cell recruitment to degenerating areas; a phenomena that occurs differentially between muscle groups
The findings of the present study reveal that exposure to the T1DM environment results in impaired skeletal muscle regeneration; a finding that is more pronounced in non-postural muscles with a greater glycolytic fiber-type composition
Summary
Type 1 diabetes mellitus (T1DM) is an autoimmune disease defined by hyperglycemia and hypoinsulinemia in the absence of exogenous insulin treatment. In the absence of a true cure, it is the complications of diabetes that define the overall health of the affected person. While the above situation is concerning in terms of muscle growth, another series of complications arise in response to muscle overuse or to muscle injury, where a multifaceted regenerative process is needed to repair/replace damaged myofibers. In this case, a severe impairment in muscle repair is observed in the skeletal muscle of T1DM; a distinct problem that is not related to any imbalances in protein metabolism [2,12]. Given intrinsic differences between muscle groups, it was unclear if the reparative responses between muscle groups were different
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