Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury
In muscle regeneration, infiltrating myeloid cells, such as macrophages mediate muscle inflammation by releasing key soluble factors. One such factor, insulin-like growth factor 1 (IGF-1), suppresses inflammatory cytokine expression and mediates macrophage polarization to anti-inflammatory phenotype...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-07-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2018.00999/full |
| _version_ | 1819364767949651968 |
|---|---|
| author | Keng-Ting Sun Kwok-Kuen Cheung Shannon W. N. Au Simon S. Yeung Ella W. Yeung |
| author_facet | Keng-Ting Sun Kwok-Kuen Cheung Shannon W. N. Au Simon S. Yeung Ella W. Yeung |
| author_sort | Keng-Ting Sun |
| collection | DOAJ |
| description | In muscle regeneration, infiltrating myeloid cells, such as macrophages mediate muscle inflammation by releasing key soluble factors. One such factor, insulin-like growth factor 1 (IGF-1), suppresses inflammatory cytokine expression and mediates macrophage polarization to anti-inflammatory phenotype during muscle injury. Previously the IGF-1Ea isoform was shown to be anti-inflammatory. Another isoform of IGF-1, mechano-growth factor (MGF), is structurally and functionally distinct from IGF-1Ea, but its role in muscle inflammation has not yet been characterized. In this study, we hypothesized that MGF expression in muscle injury modulates muscle inflammation. We first investigated changes of transcription and expression of MGF in response to skeletal muscle injury induced by cardiotoxin (CTX) in vivo. At 1–2 days post-injury, Mgf expression was significantly upregulated and positively correlated with that of inflammatory cytokines. Immunostaining revealed that infiltration of neutrophils and macrophages coincided with Mgf upregulation. Furthermore, infiltrating neutrophils and macrophages expressed Mgf, suggesting their contribution to MGF upregulation in muscle injury. Macrophages seem to be the predominant source of MGF in muscle injury, whereas neutrophil depletion did not affect muscle Mgf expression. Given the association of MGF and macrophages, we then studied whether MGF could affect macrophage infiltration and polarization. To test this, we overexpressed MGF in CTX-injured muscles and evaluated inflammatory marker expression, macrophage populations, and muscle regeneration outcomes. MGF overexpression delayed the resolution of macrophages, particularly the pro-inflammatory phenotype. This coincided with upregulation of inflammatory markers. Annexin V-based flow cytometry revealed that MGF overexpression likely delays macrophage resolution by limiting macrophage apoptosis. Although MGF overexpression did not obviously affect muscle regeneration outcomes, the findings are novel and provide insights on the physiological roles of MGF in muscle regeneration. |
| first_indexed | 2024-12-24T23:04:11Z |
| format | Article |
| id | doaj.art-b9b50c5b496b4ca59687c26491733c2c |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-24T23:04:11Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-b9b50c5b496b4ca59687c26491733c2c2022-12-21T16:35:04ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2018-07-01910.3389/fphys.2018.00999371353Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle InjuryKeng-Ting Sun0Kwok-Kuen Cheung1Shannon W. N. Au2Simon S. Yeung3Ella W. Yeung4Muscle Physiology Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Kowloon, Hong KongMuscle Physiology Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Kowloon, Hong KongCentre for Protein Science and Crystallography, School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong KongMuscle Physiology Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Kowloon, Hong KongMuscle Physiology Laboratory, Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Kowloon, Hong KongIn muscle regeneration, infiltrating myeloid cells, such as macrophages mediate muscle inflammation by releasing key soluble factors. One such factor, insulin-like growth factor 1 (IGF-1), suppresses inflammatory cytokine expression and mediates macrophage polarization to anti-inflammatory phenotype during muscle injury. Previously the IGF-1Ea isoform was shown to be anti-inflammatory. Another isoform of IGF-1, mechano-growth factor (MGF), is structurally and functionally distinct from IGF-1Ea, but its role in muscle inflammation has not yet been characterized. In this study, we hypothesized that MGF expression in muscle injury modulates muscle inflammation. We first investigated changes of transcription and expression of MGF in response to skeletal muscle injury induced by cardiotoxin (CTX) in vivo. At 1–2 days post-injury, Mgf expression was significantly upregulated and positively correlated with that of inflammatory cytokines. Immunostaining revealed that infiltration of neutrophils and macrophages coincided with Mgf upregulation. Furthermore, infiltrating neutrophils and macrophages expressed Mgf, suggesting their contribution to MGF upregulation in muscle injury. Macrophages seem to be the predominant source of MGF in muscle injury, whereas neutrophil depletion did not affect muscle Mgf expression. Given the association of MGF and macrophages, we then studied whether MGF could affect macrophage infiltration and polarization. To test this, we overexpressed MGF in CTX-injured muscles and evaluated inflammatory marker expression, macrophage populations, and muscle regeneration outcomes. MGF overexpression delayed the resolution of macrophages, particularly the pro-inflammatory phenotype. This coincided with upregulation of inflammatory markers. Annexin V-based flow cytometry revealed that MGF overexpression likely delays macrophage resolution by limiting macrophage apoptosis. Although MGF overexpression did not obviously affect muscle regeneration outcomes, the findings are novel and provide insights on the physiological roles of MGF in muscle regeneration.https://www.frontiersin.org/article/10.3389/fphys.2018.00999/fullskeletal muscle injuryinflammationmuscle regenerationinsulin-like growth factor 1mechano-growth factormyeloid cells |
| spellingShingle | Keng-Ting Sun Kwok-Kuen Cheung Shannon W. N. Au Simon S. Yeung Ella W. Yeung Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury Frontiers in Physiology skeletal muscle injury inflammation muscle regeneration insulin-like growth factor 1 mechano-growth factor myeloid cells |
| title | Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury |
| title_full | Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury |
| title_fullStr | Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury |
| title_full_unstemmed | Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury |
| title_short | Overexpression of Mechano-Growth Factor Modulates Inflammatory Cytokine Expression and Macrophage Resolution in Skeletal Muscle Injury |
| title_sort | overexpression of mechano growth factor modulates inflammatory cytokine expression and macrophage resolution in skeletal muscle injury |
| topic | skeletal muscle injury inflammation muscle regeneration insulin-like growth factor 1 mechano-growth factor myeloid cells |
| url | https://www.frontiersin.org/article/10.3389/fphys.2018.00999/full |
| work_keys_str_mv | AT kengtingsun overexpressionofmechanogrowthfactormodulatesinflammatorycytokineexpressionandmacrophageresolutioninskeletalmuscleinjury AT kwokkuencheung overexpressionofmechanogrowthfactormodulatesinflammatorycytokineexpressionandmacrophageresolutioninskeletalmuscleinjury AT shannonwnau overexpressionofmechanogrowthfactormodulatesinflammatorycytokineexpressionandmacrophageresolutioninskeletalmuscleinjury AT simonsyeung overexpressionofmechanogrowthfactormodulatesinflammatorycytokineexpressionandmacrophageresolutioninskeletalmuscleinjury AT ellawyeung overexpressionofmechanogrowthfactormodulatesinflammatorycytokineexpressionandmacrophageresolutioninskeletalmuscleinjury |