MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice
Abstract Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we d...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012993 |
| _version_ | 1797282195390332928 |
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| author | Ning Ran Caorui Lin Ling Leng Gang Han Mengyuan Geng Yingjie Wu Scott Bittner Hong M Moulton HaiFang Yin |
| author_facet | Ning Ran Caorui Lin Ling Leng Gang Han Mengyuan Geng Yingjie Wu Scott Bittner Hong M Moulton HaiFang Yin |
| author_sort | Ning Ran |
| collection | DOAJ |
| description | Abstract Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we demonstrate that MOTS‐c, a mitochondria‐derived bioactive peptide, with an intrinsic muscle‐targeting property, augmented glycolytic flux and energy production capacity of dystrophic muscles in vitro and in vivo, resulting in enhanced phosphorodiamidate morpholino oligomer (PMO) uptake and activity in mdx mice. Long‐term repeated administration of MOTS‐c (500 μg) and PMO at the dose of 12.5 mg/kg/week for 3 weeks followed by 12.5 mg/kg/month for 3 months (PMO‐M) induced therapeutic levels of dystrophin expression in peripheral muscles, with up to 25‐fold increase in diaphragm of mdx mice over PMO alone. PMO‐M improved muscle function and pathologies in mdx mice without detectable toxicity. Our results demonstrate that MOTS‐c enables enhanced PMO uptake and activity in dystrophic muscles by providing energy and may have therapeutic implications for exon‐skipping therapeutics in DMD and other energy‐deficient disorders. |
| first_indexed | 2024-03-07T17:09:31Z |
| format | Article |
| id | doaj.art-1af05cb29506438185e1117e62e7cc1f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:09:31Z |
| publishDate | 2021-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-1af05cb29506438185e1117e62e7cc1f2024-03-03T01:22:42ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-02-01132n/an/a10.15252/emmm.202012993MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic miceNing Ran0Caorui Lin1Ling Leng2Gang Han3Mengyuan Geng4Yingjie Wu5Scott Bittner6Hong M Moulton7HaiFang Yin8Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Department of Cell Biology Tianjin Medical University Tianjin ChinaTianjin Key Laboratory of Cellular Homeostasis and Human Diseases & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Department of Cell Biology Tianjin Medical University Tianjin ChinaTianjin Key Laboratory of Cellular Homeostasis and Human Diseases & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Department of Cell Biology Tianjin Medical University Tianjin ChinaSchool of Medical Laboratory Tianjin Medical University Tianjin ChinaTianjin Key Laboratory of Cellular Homeostasis and Human Diseases & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Department of Cell Biology Tianjin Medical University Tianjin ChinaTianjin Key Laboratory of Cellular Homeostasis and Human Diseases & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Department of Cell Biology Tianjin Medical University Tianjin ChinaBiomedical Sciences College of Veterinary Medicine Oregon State University Corvallis OR USABiomedical Sciences College of Veterinary Medicine Oregon State University Corvallis OR USATianjin Key Laboratory of Cellular Homeostasis and Human Diseases & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Department of Cell Biology Tianjin Medical University Tianjin ChinaAbstract Antisense oligonucleotide (AO)‐mediated exon‐skipping therapies show promise in Duchenne muscular dystrophy (DMD), a devastating muscular disease caused by frame‐disrupting mutations in the DMD gene. However, insufficient systemic delivery remains a hurdle to clinical deployment. Here, we demonstrate that MOTS‐c, a mitochondria‐derived bioactive peptide, with an intrinsic muscle‐targeting property, augmented glycolytic flux and energy production capacity of dystrophic muscles in vitro and in vivo, resulting in enhanced phosphorodiamidate morpholino oligomer (PMO) uptake and activity in mdx mice. Long‐term repeated administration of MOTS‐c (500 μg) and PMO at the dose of 12.5 mg/kg/week for 3 weeks followed by 12.5 mg/kg/month for 3 months (PMO‐M) induced therapeutic levels of dystrophin expression in peripheral muscles, with up to 25‐fold increase in diaphragm of mdx mice over PMO alone. PMO‐M improved muscle function and pathologies in mdx mice without detectable toxicity. Our results demonstrate that MOTS‐c enables enhanced PMO uptake and activity in dystrophic muscles by providing energy and may have therapeutic implications for exon‐skipping therapeutics in DMD and other energy‐deficient disorders.https://doi.org/10.15252/emmm.202012993duchenne muscular dystrophyenergyexon‐skippingMOTS‐cPMO |
| spellingShingle | Ning Ran Caorui Lin Ling Leng Gang Han Mengyuan Geng Yingjie Wu Scott Bittner Hong M Moulton HaiFang Yin MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice EMBO Molecular Medicine duchenne muscular dystrophy energy exon‐skipping MOTS‐c PMO |
| title | MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice |
| title_full | MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice |
| title_fullStr | MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice |
| title_full_unstemmed | MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice |
| title_short | MOTS‐c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice |
| title_sort | mots c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice |
| topic | duchenne muscular dystrophy energy exon‐skipping MOTS‐c PMO |
| url | https://doi.org/10.15252/emmm.202012993 |
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