Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle.
Systemic 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 un...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3741394?pdf=render |
| _version_ | 1818479043334373376 |
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| author | Matthew P Krause Dhuha Al-Sajee Donna M D'Souza Irena A Rebalka Jasmin Moradi Michael C Riddell Thomas J Hawke |
| author_facet | Matthew P Krause Dhuha Al-Sajee Donna M D'Souza Irena A Rebalka Jasmin Moradi Michael C Riddell Thomas J Hawke |
| author_sort | Matthew P Krause |
| collection | DOAJ |
| description | Systemic 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.Here 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.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. |
| first_indexed | 2024-12-10T09:56:02Z |
| format | Article |
| id | doaj.art-566c928d8d5346d39d79760e8a2dfefd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T09:56:02Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-566c928d8d5346d39d79760e8a2dfefd2022-12-22T01:53:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0188e7097110.1371/journal.pone.0070971Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle.Matthew P KrauseDhuha Al-SajeeDonna M D'SouzaIrena A RebalkaJasmin MoradiMichael C RiddellThomas J HawkeSystemic 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.Here 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.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.http://europepmc.org/articles/PMC3741394?pdf=render |
| spellingShingle | Matthew P Krause Dhuha Al-Sajee Donna M D'Souza Irena A Rebalka Jasmin Moradi Michael C Riddell Thomas J Hawke Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. PLoS ONE |
| title | Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. |
| title_full | Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. |
| title_fullStr | Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. |
| title_full_unstemmed | Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. |
| title_short | Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. |
| title_sort | impaired macrophage and satellite cell infiltration occurs in a muscle specific fashion following injury in diabetic skeletal muscle |
| url | http://europepmc.org/articles/PMC3741394?pdf=render |
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