Sodium phenylbutyrate reverses lysosomal dysfunction and decreases amyloid-β42 in an in vitro-model of inclusion-body myositis.
Sporadic inclusion-body myositis (s-IBM) is a severe, progressive muscle disease for which there is no enduring treatment. Pathologically characteristic are vacuolated muscle fibers having: accumulations of multi-protein aggregates, including amyloid-β(Aβ) 42 and its toxic oligomers; increased γ-secretase activity; and impaired autophagy. Cultured human muscle fibers with experimentally-impaired autophagy recapitulate some of the s-IBM muscle abnormalities, including vacuolization and decreased activity of lysosomal enzymes, accompanied by increased Aβ42, Aβ42 oligomers, and increased γ-secretase activity. Sodium phenylbutyrate (NaPB) is an orally bioavailable small molecule approved by the FDA for treatment of urea-cycle disorders. Here we describe that NaPB treatment reverses lysosomal dysfunction in an in vitro model of inclusion-body myositis, involving cultured human muscle fibers. NaPB treatment improved lysosomal activity, decreased Aβ42 and its oligomers, decreased γ-secretase activity, and virtually prevented muscle-fiber vacuolization. Accordingly, NaPB might be considered a potential treatment of s-IBM patients.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA.
Anna
A
Nogalska
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA.
Carla
C
D'Agostino
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA.
W King
WK
Engel
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA. Electronic address: askanas@usc.edu.
Valerie
V
Askanas
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D002402:Cathepsin D / Q000378:metabolism; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004852:Epoxy Compounds / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D013843:Thiazines / Q000494:pharmacology*; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004852:Epoxy Compounds; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D013843:Thiazines; C075222:amyloid beta-protein (1-42); C092940:cathestatin B; C546253:sodium phenothiazinate; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D053829:Amyloid Precursor Protein Secretases; D002402:Cathepsin D
Amyloid-β42, amyloid-β42-oligomers; Autophagy; Cathepsin B; Cathepsin D; Cultured human muscle fibers; Lysosomal-activity; Sodium phenylbutyrate; Sporadic-inclusion body myositis; γ-Secretase