Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle
Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneratio...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/13/4575 |
| _version_ | 1797564017928044544 |
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| author | Fasih Ahmad Rahman Sarah Anne Angus Kyle Stokes Phillip Karpowicz Matthew Paul Krause |
| author_facet | Fasih Ahmad Rahman Sarah Anne Angus Kyle Stokes Phillip Karpowicz Matthew Paul Krause |
| author_sort | Fasih Ahmad Rahman |
| collection | DOAJ |
| description | Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses. |
| first_indexed | 2024-03-10T18:51:24Z |
| format | Article |
| id | doaj.art-7b3ad4041eef49f3983b6b0c40d502cf |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T18:51:24Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7b3ad4041eef49f3983b6b0c40d502cf2023-11-20T05:08:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012113457510.3390/ijms21134575Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal MuscleFasih Ahmad Rahman0Sarah Anne Angus1Kyle Stokes2Phillip Karpowicz3Matthew Paul Krause4Department of Kinesiology, University of Windsor. Windsor, ON N9B 3P4, CanadaDepartment of Kinesiology, University of Windsor. Windsor, ON N9B 3P4, CanadaDepartment of Biomedical Sciences, University of Windsor. Windsor, ON N9B 3P4, CanadaDepartment of Biomedical Sciences, University of Windsor. Windsor, ON N9B 3P4, CanadaDepartment of Kinesiology, University of Windsor. Windsor, ON N9B 3P4, CanadaRegenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.https://www.mdpi.com/1422-0067/21/13/4575skeletal muscleregenerationextracellular matrixmacrophageplasminogen activator inhibitor-1aging |
| spellingShingle | Fasih Ahmad Rahman Sarah Anne Angus Kyle Stokes Phillip Karpowicz Matthew Paul Krause Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle International Journal of Molecular Sciences skeletal muscle regeneration extracellular matrix macrophage plasminogen activator inhibitor-1 aging |
| title | Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle |
| title_full | Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle |
| title_fullStr | Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle |
| title_full_unstemmed | Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle |
| title_short | Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle |
| title_sort | impaired ecm remodeling and macrophage activity define necrosis and regeneration following damage in aged skeletal muscle |
| topic | skeletal muscle regeneration extracellular matrix macrophage plasminogen activator inhibitor-1 aging |
| url | https://www.mdpi.com/1422-0067/21/13/4575 |
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