Pathogenic considerations in sporadic inclusion-body myositis, a degenerative muscle disease associated with aging and abnormalities of myoproteostasis.
The pathogenesis of sporadic inclusion-body myositis (s-IBM) is complex; it involves multidimensional pathways and the most critical issues are still unresolved. The onset of muscle fiber damage is age related and the disease is slowly, but inexorably, progressive. Muscle fiber degeneration and mononuclear cell inflammation are major components of s-IBM pathology, but which is precedent and how they interrelate is not known. There is growing evidence that aging of the muscle fiber associated with intramyofiber accumulation of conformationally modified proteins plays a primary pathogenic role leading to muscle fiber destruction. Here, we review the presumably most important known molecular abnormalities that occur in s-IBM myofibers and that likely contribute to s-IBM pathogenesis. Abnormal accumulation within the fibers of multiprotein aggregates (several of which are congophilic and, therefore, generically called "amyloid") may result from increased transcription of several proteins, their abnormal posttranslational modifications and misfolding, and inadequate protein disposal, that is, abnormal "myoproteostasis," which is combined with and may be provoked or abetted by an aging intracellular milieu. The potential cytotoxicity of accumulated amyloid β protein (Aβ42) and its oligomers, phosphorylated tau in the form of paired helical filaments and α-synuclein, and the putative pathogenic role and cause of the mitochondrial abnormalities and oxidative stress are reviewed. On the basis of our experimental evidence, potential interventions in the complex, interwoven pathogenic cascade of s-IBM are suggested.
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA. askanas@usc.edu
Valerie
V
Askanas
W King
WK
Engel
Anna
A
Nogalska
D000375:Aging / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D001343:Autophagy; D001706:Biopsy; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use; D008931:Mitochondria, Muscle / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism; D010654:Phenylbutyrates / Q000627:therapeutic use; D059808:Polyphenols / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018020:Lithium Compounds; D009124:Muscle Proteins; D010446:Peptide Fragments; D010654:Phenylbutyrates; D059808:Polyphenols; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease