Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition.
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and there is no successful treatment. We summarize our most recent findings, which provide a better understanding of the steps in the pathogenetic cascade. We suggest that s-IBM is primarily a myodegenerative disease. Intriguing are the phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer disease, the most common neurodegenerative disease of older persons. In s-IBM, abnormal accumulation of the amyloid-beta (Abeta) precursor protein and its proteolytic fragment, Abeta, associated with the aging intracellular milieu of the muscle fiber, appear to be key upstream pathogenic events. We propose that the identified abnormal accumulation, misfolding, and aggregation of proteins, perhaps provoked by the aging milieu and aggravated by the oxidative stress, lead to the s-IBM-specific vacuolar degeneration and atrophy of muscle fibers.
Askanas
Valerie
V
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA. askanas@usc.edu
Engel
W King
WK
D000368:Aged; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011487:Protein Conformation; D017510:Protein Folding; D014617:Vacuoles / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D009124:Muscle Proteins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease