title: Downregulation of E3 ubiquitin ligases and mitophagy-related genes in skeletal muscle of physically inactive, frail older women: a cross-sectional comparison.
abstract: OBJECTIVE
  Reduced lean mass and physical function is a characteristic of frailty. However, it is currently unknown if proteolysis through the E3 ubiquitin ligases and the autophagic lysosomal pathway is dysregulated in inactive frail older women. The purpose of this study was to determine the expression of key markers of ubiquitin-mediated and autophagic lysosomal proteolysis in inactive (N = 7) compared with active (N = 7) older women.
  
  
  METHODS
  Strength, mobility, leg lean mass, and physical activity assessment were used to characterize activity levels and frailty in older women. Vastus lateralis biopsies were collected after an overnight fast and were assessed for gene and protein targets related to E3 ubiquitin ligases and the autophagic lysosomal system.
  
  
  RESULTS
  We found that AMP-activated protein kinase alpha (Thr172) was increased (p = .045), and forkhead box O3A (FOXO3A) gene expression (p = .047) was lower in inactive frail older women. Foxo3a (Ser253), Beclin1 (Ser93/96), and class III phosphatidylinositol-3-kinase (VPS34) protein expression were not different between the groups (p > .05). Neural precursor cell-expressed developmentally downregulated protein 4, muscle ring finger 1, muscle atrophy F-box, and the autophagy/mitophagy gene expression markers, Beclin1, autophagy-related-7, BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), dynamin-related protein 1, and Parkinson protein 2 (PARKIN) were lower in inactive frail older women (p < .05). Autophagy/mitophagy markers were positively correlated with the 6-minute walk and leg lean mass (p < .05).
  
  
  CONCLUSIONS
  We conclude that physical inactivity in frail older women is associated with a downregulation of ubiquitin-mediated and autophagic lysosomal skeletal muscle gene expression, perhaps related to low muscle mass and poor physical function.
authors: Department of Physical Therapy, micah.drummond@hsc.utah.edu.
authors: Micah J
authors: MJ
authors: Drummond
authors: Department of Physical Therapy.
authors: Odessa
authors: O
authors: Addison
authors: Department of Physical Therapy.
authors: Lucille
authors: L
authors: Brunker
authors: Department of Cardiovascular Genetics, and.
authors: Paul N
authors: PN
authors: Hopkins
authors: Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah.
authors: Donald A
authors: DA
authors: McClain
authors: Department of Physical Therapy.
authors: Paul C
authors: PC
authors: LaStayo
authors: Department of Physical Therapy.
authors: Robin L
authors: RL
authors: Marcus
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000071186:Beclin-1; D003430:Cross-Sectional Studies; D015536:Down-Regulation / Q000502:physiology; D034281:Dynamins; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D016330:Frail Elderly; D020558:GTP Phosphohydrolases / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D063306:Mitophagy / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology; D009133:Muscular Atrophy / Q000503:physiopathology; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation / Q000502:physiology; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D055948:Sarcopenia / Q000235:genetics / Q000503:physiopathology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; C090121:BNIP3 protein, human; D000071186:Beclin-1; D056827:Endosomal Sorting Complexes Required for Transport; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D000070584:Tripartite Motif Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D055372:AMP-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Aging; Atrophy; Autophagy; Mitochondrial dysfunction; Mobility.