EXCEED THE SPACE PROVIDED. Sporadic inclusion-body myositis (s-IBM) is a progressive, highly debilitating, and the most common nuscle disease of older persons (over age 60). An intriguing aspect of s-IBM is that its muscle fiber phenotype has features remarkably similar to those of Alzheimer Disease (AD) brain ('IBM-AD phenotype'), including abnormal accumulations of: 3-amyloid precursor protein ( APP) and of several other proteins accumulated in AD brain. Another similarity to AD is the presence of hereditary forms, termed 'hereditary inclusion-body nyopathies (h-IBM)', which clinically are manifest earlier than s-IBM, but have a muscle-fiber phenotype identical to, though apparently somewhat less advanced than, that of s-IBM. Similarly to AD brain, abnormal nuscle fibers of s- and h-IBM have evidence ofoxidative stress. Abnormalaccumulation of (3APP epitopes appears toprecede other abnormalities in s- and h-IBM muscle, in vivo and in vitro. Therefore, we propose that JAPP overexpressiom (whole molecule and/or A(3fragment) in the milieu of aged (s-IBM) or genetically- abnormal adult (h-IBM) muscle fibers causes molecular disturbances leading to oxidative stress, which then causes the IBM-specific vacuolar muscle-fiber degeneration and expression of the IBM-AD phenotype. This >roposal addresses the schedule, and therefore possible mechanisms, of early steps in the pathogenic cascade. It involves: 1)three long-term culture models, namely, a) a spontaneous model utilizing cultures of biopsied muscle of h-IBM; b) a spontaneous model utilizing cultures of s-IBM muscle; and c) an induced model utilizing matured cultured normal human muscle fibers into which is transferred the (3APP gene; and 2) an induced in vivo aged-rat nodel based on transfer of the 3APP gene into aged-rat gastrocnemius muscle. Anti-oxidant treatments, including estrogens, will be done on abnormal cultures. We postulate that in vivo aging of the involved tissues may be a predisposing factor(s) in both the IBM's and the ADgroup, especially in the sporadic, more common, forms of each. Because our type of cultured spontaneous and induced models of the human tissue actually affected in the >atient are not available to study brain involvement in the AD's, possibly our results may provide important information relevant to the pathogenesis and treatment of the AD's. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Snyder, Stephen D
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University of Southern California
Schools of Medicine
Los Angeles
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Askanas, Valerie; Engel, W King; Nogalska, Anna (2015) Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy. Biochim Biophys Acta 1852:633-43
Nogalska, Anna; D'Agostino, Carla; Engel, W King et al. (2015) Activation of the Unfolded Protein Response in Sporadic Inclusion-Body Myositis but Not in Hereditary GNE Inclusion-Body Myopathy. J Neuropathol Exp Neurol 74:538-46
Askanas, Valerie; Engel, W King; Nogalska, Anna (2012) Pathogenic considerations in sporadic inclusion-body myositis, a degenerative muscle disease associated with aging and abnormalities of myoproteostasis. J Neuropathol Exp Neurol 71:680-93
Nogalska, Anna; D'Agostino, Carla; Engel, W King et al. (2012) Activation of the ?-secretase complex and presence of ?-secretase-activating protein may contribute to A?42 production in sporadic inclusion-body myositis muscle fibers. Neurobiol Dis 48:141-9
D'Agostino, C; Nogalska, A; Engel, W K et al. (2011) In sporadic inclusion body myositis muscle fibres TDP-43-positive inclusions are less frequent and robust than p62 inclusions, and are not associated with paired helical filaments. Neuropathol Appl Neurobiol 37:315-20
Terracciano, Chiara; Nogalska, Anna; Engel, W King et al. (2010) In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis. J Neurochem 112:389-96
Nogalska, Anna; Engel, W King; Askanas, Valerie (2010) Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress. Neurosci Lett 474:140-3
Nogalska, Anna; D'Agostino, Carla; Engel, W King et al. (2010) Decreased SIRT1 deacetylase activity in sporadic inclusion-body myositis muscle fibers. Neurobiol Aging 31:1637-48
Nogalska, Anna; D'Agostino, Carla; Engel, W King et al. (2010) Novel demonstration of amyloid-? oligomers in sporadic inclusion-body myositis muscle fibers. Acta Neuropathol 120:661-6
Nogalska, Anna; D'Agostino, Carla; Terracciano, Chiara et al. (2010) Impaired autophagy in sporadic inclusion-body myositis and in endoplasmic reticulum stress-provoked cultured human muscle fibers. Am J Pathol 177:1377-87

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