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.
Keywords:
MTOR; VCP; autophagy; myopathy; rapamycin.
MeSH terms
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Adenosine Triphosphatases / metabolism*
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Animals
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Autophagy / drug effects*
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Cell Cycle Proteins / metabolism*
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Disease Models, Animal
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Frontotemporal Dementia / metabolism
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Frontotemporal Dementia / pathology
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Humans
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Mice
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Muscle Weakness / metabolism*
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Muscle Weakness / pathology*
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Mutant Proteins / metabolism
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Myositis, Inclusion Body / metabolism*
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Myositis, Inclusion Body / pathology*
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Osteitis Deformans / metabolism
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Osteitis Deformans / pathology
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Phagosomes / drug effects
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Phagosomes / metabolism
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Signal Transduction / drug effects
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases / metabolism
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Valosin Containing Protein
Substances
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Cell Cycle Proteins
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Mutant Proteins
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TOR Serine-Threonine Kinases
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Adenosine Triphosphatases
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VCP protein, human
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Valosin Containing Protein
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Vcp protein, mouse
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Sirolimus