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PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle
Duchenne muscular dystrophy (DMD) is caused by the absence of functional dystrophin protein and results in progressive muscle wasting. Dystrophin deficiency leads to a host of dysfunctional cellular processes including impaired autophagy. Autophagic dysfunction appears to be due, at least in part, t...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048376/ https://www.ncbi.nlm.nih.gov/pubmed/32109352 http://dx.doi.org/10.14814/phy2.14383 |
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author | Spaulding, Hannah R. Ludwig, Amanda K. Hollinger, Katrin Hudson, Matthew B. Selsby, Joshua T. |
author_facet | Spaulding, Hannah R. Ludwig, Amanda K. Hollinger, Katrin Hudson, Matthew B. Selsby, Joshua T. |
author_sort | Spaulding, Hannah R. |
collection | PubMed |
description | Duchenne muscular dystrophy (DMD) is caused by the absence of functional dystrophin protein and results in progressive muscle wasting. Dystrophin deficiency leads to a host of dysfunctional cellular processes including impaired autophagy. Autophagic dysfunction appears to be due, at least in part, to decreased lysosomal abundance mediated by decreased nuclear localization of transcription factor EB (TFEB), a transcription factor responsible for lysosomal biogenesis. PGC‐1α overexpression decreased disease severity in dystrophin‐deficient skeletal muscle and increased PGC‐1α has been linked to TFEB activation in healthy muscle. The purpose of this study was to determine the extent to which PGC‐1α overexpression increased nuclear TFEB localization, increased lysosome abundance, and increased autophagosome degradation. We hypothesized that overexpression of PGC‐1α would drive TFEB nuclear translocation, increase lysosome biogenesis, and improve autophagosome degradation. To address this hypothesis, we delivered PGC‐1α via adeno‐associated virus (AAV) vector injected into the right limb of 3‐week‐old mdx mice and the contralateral limbs received a sham injection. At 6 weeks of age, this approach increased PGC‐1α transcript by 60‐fold and increased TFEB nuclear localization in gastrocnemii from PGC‐1α treated limbs by twofold compared to contralateral controls. Furthermore, lamp2, a marker of lysosome abundance, was significantly elevated in muscles from limbs overexpressing PGC‐1α. Lastly, increased LC3II and similar p62 in PGC‐1α overexpressing‐limbs compared to contralateral limbs are supportive of increased degradation of autophagosomes. These data provide mechanistic insight into PGC‐1α‐mediated benefits to dystrophin‐deficient muscle, such that increased TFEB nuclear localization in dystrophin‐deficient muscle leads to increased lysosome biogenesis and autophagy. |
format | Online Article Text |
id | pubmed-7048376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70483762020-03-05 PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle Spaulding, Hannah R. Ludwig, Amanda K. Hollinger, Katrin Hudson, Matthew B. Selsby, Joshua T. Physiol Rep Original Research Duchenne muscular dystrophy (DMD) is caused by the absence of functional dystrophin protein and results in progressive muscle wasting. Dystrophin deficiency leads to a host of dysfunctional cellular processes including impaired autophagy. Autophagic dysfunction appears to be due, at least in part, to decreased lysosomal abundance mediated by decreased nuclear localization of transcription factor EB (TFEB), a transcription factor responsible for lysosomal biogenesis. PGC‐1α overexpression decreased disease severity in dystrophin‐deficient skeletal muscle and increased PGC‐1α has been linked to TFEB activation in healthy muscle. The purpose of this study was to determine the extent to which PGC‐1α overexpression increased nuclear TFEB localization, increased lysosome abundance, and increased autophagosome degradation. We hypothesized that overexpression of PGC‐1α would drive TFEB nuclear translocation, increase lysosome biogenesis, and improve autophagosome degradation. To address this hypothesis, we delivered PGC‐1α via adeno‐associated virus (AAV) vector injected into the right limb of 3‐week‐old mdx mice and the contralateral limbs received a sham injection. At 6 weeks of age, this approach increased PGC‐1α transcript by 60‐fold and increased TFEB nuclear localization in gastrocnemii from PGC‐1α treated limbs by twofold compared to contralateral controls. Furthermore, lamp2, a marker of lysosome abundance, was significantly elevated in muscles from limbs overexpressing PGC‐1α. Lastly, increased LC3II and similar p62 in PGC‐1α overexpressing‐limbs compared to contralateral limbs are supportive of increased degradation of autophagosomes. These data provide mechanistic insight into PGC‐1α‐mediated benefits to dystrophin‐deficient muscle, such that increased TFEB nuclear localization in dystrophin‐deficient muscle leads to increased lysosome biogenesis and autophagy. John Wiley and Sons Inc. 2020-02-28 /pmc/articles/PMC7048376/ /pubmed/32109352 http://dx.doi.org/10.14814/phy2.14383 Text en © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Spaulding, Hannah R. Ludwig, Amanda K. Hollinger, Katrin Hudson, Matthew B. Selsby, Joshua T. PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
title | PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
title_full | PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
title_fullStr | PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
title_full_unstemmed | PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
title_short | PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
title_sort | pgc‐1α overexpression increases transcription factor eb nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048376/ https://www.ncbi.nlm.nih.gov/pubmed/32109352 http://dx.doi.org/10.14814/phy2.14383 |
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