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Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy

Patients with myotonic dystrophy type 1 (DM1) identify chronic fatigue as the most debilitating symptom, which manifests in part as prolonged recovery after exercise. Clinical features of DM1 result from pathogenic gain-of-function activity of transcripts containing an expanded microsatellite CUG re...

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Autores principales: Hu, Ningyan, Kim, Eunjoo, Antoury, Layal, Li, Jia, González-Pérez, Paloma, Rutkove, Seward B., Wheeler, Thurman M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787993/
https://www.ncbi.nlm.nih.gov/pubmed/33473325
http://dx.doi.org/10.1016/j.omtn.2020.11.014
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author Hu, Ningyan
Kim, Eunjoo
Antoury, Layal
Li, Jia
González-Pérez, Paloma
Rutkove, Seward B.
Wheeler, Thurman M.
author_facet Hu, Ningyan
Kim, Eunjoo
Antoury, Layal
Li, Jia
González-Pérez, Paloma
Rutkove, Seward B.
Wheeler, Thurman M.
author_sort Hu, Ningyan
collection PubMed
description Patients with myotonic dystrophy type 1 (DM1) identify chronic fatigue as the most debilitating symptom, which manifests in part as prolonged recovery after exercise. Clinical features of DM1 result from pathogenic gain-of-function activity of transcripts containing an expanded microsatellite CUG repeat (CUG(exp)). In DM1 mice, therapies targeting the CUG(exp) transcripts correct the molecular phenotype, reverse myotonia, and improve muscle pathology. However, the effect of targeted molecular therapies on fatigue in DM1 is unknown. Here, we use two mouse models of DM1, age-matched wild-type controls, an exercise-activity assay, electrical impedance myography, and therapeutic antisense oligonucleotides (ASOs) to show that exaggerated exercise-induced fatigue progresses with age, is unrelated to muscle fiber size, and persists despite correction of the molecular phenotype for 3 months. In old DM1 mice, ASO treatment combined with an exercise training regimen consisting of treadmill walking 30 min per day 6 days per week for 3 months reverse all measures of fatigue. Exercise training without ASO therapy improves some measures of fatigue without correction of the molecular pathology. Our results highlight a key limitation of ASO monotherapy for this clinically important feature and support the development of moderate-intensity exercise as an adjuvant for targeted molecular therapies of DM1.
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spelling pubmed-77879932021-01-19 Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy Hu, Ningyan Kim, Eunjoo Antoury, Layal Li, Jia González-Pérez, Paloma Rutkove, Seward B. Wheeler, Thurman M. Mol Ther Nucleic Acids Original Article Patients with myotonic dystrophy type 1 (DM1) identify chronic fatigue as the most debilitating symptom, which manifests in part as prolonged recovery after exercise. Clinical features of DM1 result from pathogenic gain-of-function activity of transcripts containing an expanded microsatellite CUG repeat (CUG(exp)). In DM1 mice, therapies targeting the CUG(exp) transcripts correct the molecular phenotype, reverse myotonia, and improve muscle pathology. However, the effect of targeted molecular therapies on fatigue in DM1 is unknown. Here, we use two mouse models of DM1, age-matched wild-type controls, an exercise-activity assay, electrical impedance myography, and therapeutic antisense oligonucleotides (ASOs) to show that exaggerated exercise-induced fatigue progresses with age, is unrelated to muscle fiber size, and persists despite correction of the molecular phenotype for 3 months. In old DM1 mice, ASO treatment combined with an exercise training regimen consisting of treadmill walking 30 min per day 6 days per week for 3 months reverse all measures of fatigue. Exercise training without ASO therapy improves some measures of fatigue without correction of the molecular pathology. Our results highlight a key limitation of ASO monotherapy for this clinically important feature and support the development of moderate-intensity exercise as an adjuvant for targeted molecular therapies of DM1. American Society of Gene & Cell Therapy 2020-11-26 /pmc/articles/PMC7787993/ /pubmed/33473325 http://dx.doi.org/10.1016/j.omtn.2020.11.014 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Hu, Ningyan
Kim, Eunjoo
Antoury, Layal
Li, Jia
González-Pérez, Paloma
Rutkove, Seward B.
Wheeler, Thurman M.
Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
title Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
title_full Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
title_fullStr Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
title_full_unstemmed Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
title_short Antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
title_sort antisense oligonucleotide and adjuvant exercise therapy reverse fatigue in old mice with myotonic dystrophy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787993/
https://www.ncbi.nlm.nih.gov/pubmed/33473325
http://dx.doi.org/10.1016/j.omtn.2020.11.014
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