Impaired Macrophage and Satellite Cell Infiltration Occurs in a Muscle-Specific Fashion Following Injury in Diabetic Skeletal Muscle

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.

Decreased Satellite Cell Number and Function in Humans and Mice With Type 1 Diabetes Is the Result of Altered Notch Signaling

“…Literature from our laboratory has demonstrated that Akita skeletal muscle displays functional deficits (17) and supports work done by others in regenerating and uninjured Akita skeletal muscle (6). We and others have established that rodents with T1D demonstrate a failure to repair after extreme damage, such as transplantation or toxin-induced injury (5,6,13,34), but the data presented here are the first to show a decline in skeletal muscle function after exposure to a mild muscle-damaging stimulus, such as eccentric exercise, and corroborates work from Howard et al (7), who found that myocytes from diabetic mice failed to repair from laser-and contraction-induced plasma membrane injuries in vitro. We predict that the decline in Akita skeletal muscle function, as demonstrated by the rapid time to exhaustion, is a result of a slow rate of muscle repair after damage, as has been identified previously (34).…”

“…Hyperglycemia observed in diabetic mice (and consistent with poorly controlled young adults with T1D [47]) coincides with enhanced Notch signaling in T1D skeletal muscle. In addition, extracellular matrix remodelling is important for SC function (13,48), and it is clear that the capacity for extracellular matrix remodelling, through reduction in matrix metalloprotease activity, is negatively affected in T1D skeletal muscle (13,30). Because these proteases (matrix metalloprotease, a disintegrin and metalloproteinase, etc.)…”

“…These mice were placed on a treadmill with a 15°downhill incline to promote eccentric exercise, as previously described (12), with modifications. Mice were tested at this specific age to compare and contrast data from a previous study completed by our laboratory that used a chemical means to induce muscle damage in this same mouse model (13).…”

Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes

“…In a genetically induced diabetic mouse model (Akita), elevated PAI-1 levels attenuated collagen turnover and, ultimately, impaired macrophage infiltration into damaged skeletal muscle. This impairment in infiltration was restored with the systemic administration of PAI-039 (29). Similarly, previous findings indicate an increase in the number of lung exudate macrophages in the presence of PAI-1, while, contrarily, the administration of a small-molecule PAI-1 inhibitor attenuated renal macrophage migration in nondiabetic animals (30,31).…”

miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice

“…In resting muscle, satellite cells are mostly quiescent; however, in response to stress or injury, these cells are activated, proliferate, and undergo differentiation to repair damaged muscle or selfrenewal to replenish the quiescent cell pool [10][11][12]. Reduced satellite cell function has been observed in patients with chronic diseases, including cancer-induced cachexia and diabetes [13,14]. Moreover, reduced muscle stem cell function may be a potentially important mechanism in the pathogenic development of age-related sarcopenia [15,16].…”