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Autophagy is Independent of Disease Progression in the Dystrophic Myocardium in Mouse and Porcine Dystrophinopathy Models
Author(s) -
Spaulding Hannah,
neman Dan,
Ross Jason,
Selsby Joshua
Publication year - 2017
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.31.1_supplement.1020.30
Subject(s) - autophagy , dystrophin , atg5 , skeletal muscle , biology , endocrinology , duchenne muscular dystrophy , medicine , cardiomyopathy , microbiology and biotechnology , heart failure , genetics , apoptosis
Dystrophinopathies are muscle diseases caused by mutations in the dystrophin gene resulting in insufficiency or absence of functional dystrophin protein. A deficiency of functional dystrophin results in membrane instability, mitochondrial dysfunction and metabolic abnormalities. Autophagy functions to remove damaged organelles, proteins and other cellular components and is emerging as an important process in dystrophic skeletal muscle, though the role of autophagy in dystrophic myocardium is currently unknown. The purpose of this investigation is to determine the extent to which autophagy is affected by disease progression in cardiac muscle. We hypothesized that dystrophin deficiency would result in progressive autophagic dysfunction in the heart. To address this hypothesis protein abundances from 7 week and 17 months old mdx mice were compared to C57 age‐matched controls. Surprisingly, measures of autophagic initiation, phosphorylated AMPK T172, phosphorylated UNC‐51‐like kinase 1 (ULK1) and Beclin‐1, were similar between all groups. In addition, autophagy‐related gene 5 (ATG5) and the ATG 12/5 complex, proteins indicative of autophagosome formation, were similar between groups. Furthermore, LC3I and the LC3I lipidation product, LC3II, were similar to age‐matched controls and markers of autophagic flux, the LC3II/I ratio and p62, were also similar between groups. To confirm that autophagy was independent of disease progression, heart tissue from a novel porcine dystrophinopathy model was also evaluated. Hearts were collected from healthy and affected male littermates at 3 and 12 months of age. This porcine model is dystrophin insufficient with necrotic lesions apparent at 12 months but not at 3 months of age. Consistent with our findings in the mdx mouse, protein abundances of phosphorylated ULK1, Beclin, ATG12/5 complex formation, LC3I, and p62 were similar between all groups. LC3II and the LC3II/I ratio were decreased as a function of age but did not differ with dystrophin deficiency. These data suggest that disease progression does not cause autophagic dysfunction in dystrophic myocardium. Support or Funding Information This work was supported in part by NIH R21 NS079603 and the Duchenne Alliance.