PGC-1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin-deficient skeletal muscle Spaulding, Hannah Selsby, Joshua Ludwig, Amanda Hollinger, Katrin Hudson, Matthew Selsby, Joshua
dc.contributor.department Animal Science 2021-01-28T22:01:28.000 2021-02-24T21:13:44Z 2021-02-24T21:13:44Z Wed Jan 01 00:00:00 UTC 2020 2020-02-01
dc.description.abstract <p>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.</p>
dc.description.comments <p>This article is published as Spaulding, Hannah R., Amanda K. Ludwig, Katrin Hollinger, Matthew B. Hudson, and Joshua T. Selsby. "PGC‐1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin‐deficient skeletal muscle." <em>Physiological reports</em> 8, no. 4 (2020): e14383. doi: <a href="">10.14814/phy2.14383</a>.</p>
dc.format.mimetype application/pdf
dc.identifier archive/
dc.identifier.articleid 1689
dc.identifier.contextkey 21303425
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath ans_pubs/699
dc.language.iso en
dc.source.bitstream archive/|||Sat Jan 15 01:31:36 UTC 2022
dc.source.uri 10.14814/phy2.14383
dc.subject.disciplines Animal Experimentation and Research
dc.subject.disciplines Animal Sciences
dc.subject.disciplines Cellular and Molecular Physiology
dc.subject.keywords autophagy
dc.subject.keywords DMD
dc.subject.keywords dystrophin
dc.subject.keywords mdx
dc.subject.keywords TFEB
dc.title PGC-1α overexpression increases transcription factor EB nuclear localization and lysosome abundance in dystrophin-deficient skeletal muscle
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication 6f883eb1-dd01-4874-8949-fa2eaef5899a
relation.isOrgUnitOfPublication 85ecce08-311a-441b-9c4d-ee2a3569506f
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