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PGC‐1α Overexpression Increases Lysosome Abundance and Autophagy in Dystrophic Skeletal Muscle
Author(s) -
Ludwig Amanda,
Spaulding Hannah Rose,
Hudson Matthew,
Selsby Joshua
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.908.1
Subject(s) - tfeb , autophagy , lysosome , duchenne muscular dystrophy , endocrinology , medicine , autophagosome , biology , microbiology and biotechnology , atg16l1 , skeletal muscle , chemistry , biochemistry , enzyme , apoptosis
Duchenne muscular dystrophy is a severe muscle wasting disease caused by the absence of functional dystrophin protein. We have previously established that increased peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) pathway activity is therapeutic in dystrophic muscle. The purpose of this study was to determine the extent to which increased PGC‐1α pathway activity increased nuclear localization and activity of transcription factor EB (TFEB), a transcription factor that leads to lysosomal biogenesis. We hypothesized that increased PGC‐1α pathway activity would increase TFEB nuclear migration, lysosome abundance, and the restoration of impaired autophagosome degradation. To address this hypothesis, 3‐week‐old mdx mice were injected in one limb with an adeno‐associated virus that drives PGC‐1α gene expression and the other limb was injected with an empty capsid. Animals were sacrificed at 6 weeks of age and the gastrocnemii were harvested. PGC‐1α overexpression was confirmed by qPCR. Total TFEB protein abundance was similar between groups, however, nuclear TFEB was significantly increased in PGC‐1α treated limbs consistent with our hypothesis. We also discovered that Lamp2, a lysosomal marker, was significantly elevated in PGC‐1α treated muscle. Finally, abundance of autophagy‐related proteins were compared between treated and control gastrocnemii of mdx mice as well as to gastrocnemii from adult C57 mice. LC3 II, an indicator of autophagosome formation, was significantly elevated in PGC‐1α‐treated limbs compared to both the C57 and mdx‐control muscles. However, p62, an inverse correlate of autophagosome degradation, was similar between groups suggesting elevated degradation of autophagosomes in PGC‐1α treated limbs. These data suggest increased PGC‐1α pathway activity increased lysosomal degradation of autophagosomes in dystrophic muscle, likely through a TFEB‐mediated mechanism. Support or Funding Information Supported by the American Physiological Society. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .