title: Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy.
abstract: Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS.
authors: Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA.
authors: James K
authors: JK
authors: Ching
authors: Conrad C
authors: CC
authors: Weihl
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018908:Muscle Weakness / Q000378:metabolism* / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology*; D010001:Osteitis Deformans / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D050505:Mutant Proteins; D058570:TOR Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; D020123:Sirolimus
keywords: MTOR; VCP; autophagy; myopathy; rapamycin