Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology
Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibit...
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| Format: | Article |
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MDPI AG
2021-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/9/1506 |
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| author | Aqsa Iqbal Ulrike May Stuart N. Prince Tero A.H. Järvinen Ahlke Heydemann |
| author_facet | Aqsa Iqbal Ulrike May Stuart N. Prince Tero A.H. Järvinen Ahlke Heydemann |
| author_sort | Aqsa Iqbal |
| collection | DOAJ |
| description | Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy. |
| first_indexed | 2024-03-10T07:18:22Z |
| format | Article |
| id | doaj.art-76ad9a7b703d4761adc17e2a29c3f0eb |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T07:18:22Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-76ad9a7b703d4761adc17e2a29c3f0eb2023-11-22T14:48:47ZengMDPI AGPharmaceutics1999-49232021-09-01139150610.3390/pharmaceutics13091506Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy PathologyAqsa Iqbal0Ulrike May1Stuart N. Prince2Tero A.H. Järvinen3Ahlke Heydemann4Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USAFaculty of Medicine and Health Technology, Tampere University, 33014 Tampere, FinlandFaculty of Medicine and Health Technology, Tampere University, 33014 Tampere, FinlandFaculty of Medicine and Health Technology, Tampere University, 33014 Tampere, FinlandDepartment of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USAMuscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy.https://www.mdpi.com/1999-4923/13/9/1506vascular homing peptidemuscular dystrophyfibrosistransforming growth factor-β1 (TGFβ1)decorinmdx |
| spellingShingle | Aqsa Iqbal Ulrike May Stuart N. Prince Tero A.H. Järvinen Ahlke Heydemann Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology Pharmaceutics vascular homing peptide muscular dystrophy fibrosis transforming growth factor-β1 (TGFβ1) decorin mdx |
| title | Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology |
| title_full | Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology |
| title_fullStr | Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology |
| title_full_unstemmed | Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology |
| title_short | Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology |
| title_sort | systemically administered homing peptide targets dystrophic lesions and delivers transforming growth factor β tgfβ inhibitor to attenuate murine muscular dystrophy pathology |
| topic | vascular homing peptide muscular dystrophy fibrosis transforming growth factor-β1 (TGFβ1) decorin mdx |
| url | https://www.mdpi.com/1999-4923/13/9/1506 |
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