Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations
miR-486 is a myogenic microRNA, and its reduced skeletal muscle expression is observed in muscular dystrophy. Transgenic overexpression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues muscular dystrophy phenotype. We had previously demonstrated reduced circulating an...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122000580 |
| _version_ | 1818365658593755136 |
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| author | Ruizhong Wang Brijesh Kumar Emma H. Doud Amber L. Mosley Matthew S. Alexander Louis M. Kunkel Harikrishna Nakshatri |
| author_facet | Ruizhong Wang Brijesh Kumar Emma H. Doud Amber L. Mosley Matthew S. Alexander Louis M. Kunkel Harikrishna Nakshatri |
| author_sort | Ruizhong Wang |
| collection | DOAJ |
| description | miR-486 is a myogenic microRNA, and its reduced skeletal muscle expression is observed in muscular dystrophy. Transgenic overexpression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues muscular dystrophy phenotype. We had previously demonstrated reduced circulating and skeletal muscle miR-486 levels with accompanying skeletal muscle defects in mammary tumor models. To determine whether skeletal muscle miR-486 is functionally similar in dystrophies and cancer, we performed functional limitations and biochemical studies of skeletal muscles of MMTV-Neu mice that mimic HER2+ breast cancer and MMTV-PyMT mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu mice. In this model, miR-486 reversed cancer-induced skeletal muscle changes, including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of hnRNPA0 and SRSF10 phosphorylation. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss of function causes congenital muscular dystrophy. Complementing these beneficial effects on muscle, miR-486 indirectly reduced tumor growth and improved survival, which is likely due to systemic effects of miR-486 on production of pro-inflammatory cytokines such as IL-6. Thus, similar to dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden. |
| first_indexed | 2024-12-13T22:23:46Z |
| format | Article |
| id | doaj.art-a2b5f758d06c43e78d62dda8ba2f597c |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-13T22:23:46Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-a2b5f758d06c43e78d62dda8ba2f597c2022-12-21T23:29:17ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-06-0128231248Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitationsRuizhong Wang0Brijesh Kumar1Emma H. Doud2Amber L. Mosley3Matthew S. Alexander4Louis M. Kunkel5Harikrishna Nakshatri6Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Pediatrics, Division of Neurology, University of Alabama at Birmingham and Children’s of Alabama, Birmingham, AL 35294, USABoston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Richard L Roudebush VA Medical Center, Indianapolis, IN 46202, USA; Corresponding author Harikrishna Nakshatri, Department of Surgery, Indiana University School of Medicine, 980 West Walnut Street, C218C, Indianapolis, IN 46202, USA.miR-486 is a myogenic microRNA, and its reduced skeletal muscle expression is observed in muscular dystrophy. Transgenic overexpression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues muscular dystrophy phenotype. We had previously demonstrated reduced circulating and skeletal muscle miR-486 levels with accompanying skeletal muscle defects in mammary tumor models. To determine whether skeletal muscle miR-486 is functionally similar in dystrophies and cancer, we performed functional limitations and biochemical studies of skeletal muscles of MMTV-Neu mice that mimic HER2+ breast cancer and MMTV-PyMT mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu mice. In this model, miR-486 reversed cancer-induced skeletal muscle changes, including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of hnRNPA0 and SRSF10 phosphorylation. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss of function causes congenital muscular dystrophy. Complementing these beneficial effects on muscle, miR-486 indirectly reduced tumor growth and improved survival, which is likely due to systemic effects of miR-486 on production of pro-inflammatory cytokines such as IL-6. Thus, similar to dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden.http://www.sciencedirect.com/science/article/pii/S2162253122000580DMD:non-coding RNAsbreast cancerfunctional limitationsmiR-486skeletal muscle |
| spellingShingle | Ruizhong Wang Brijesh Kumar Emma H. Doud Amber L. Mosley Matthew S. Alexander Louis M. Kunkel Harikrishna Nakshatri Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations Molecular Therapy: Nucleic Acids DMD:non-coding RNAs breast cancer functional limitations miR-486 skeletal muscle |
| title | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations |
| title_full | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations |
| title_fullStr | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations |
| title_full_unstemmed | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations |
| title_short | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations |
| title_sort | skeletal muscle specific overexpression of mir 486 limits mammary tumor induced skeletal muscle functional limitations |
| topic | DMD:non-coding RNAs breast cancer functional limitations miR-486 skeletal muscle |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122000580 |
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