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Title: Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [1] ;  [1] ;  [4] ;  [4] ;  [5] ;  [6]
  1. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Medicine
  2. Mayo Clinic, rochester, MN (United States)
  3. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Nutrition
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division
  5. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Medicine; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Radiology
  6. Univ. of Tennessee, Knoxville, TN (United States). Dept. of Medicine; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Radiology
Publication Date:
OSTI Identifier:
1260653
Grant/Contract Number:
AC05-00OR22725; R01DK079984
Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 9; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Research Org:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES