Abstract
Valosin-containing protein (VCP) mutations cause inclusion body myopathy with Paget disease and frontotemporal dementia. However, the mechanisms by which mutant VCP triggers degeneration remain unknown. Here, we investigated the role of VCP in cellular stress and found that the oxidative stressor arsenite and heat shock-activated stress responses evident by T-intracellular antigen-1-positive granules in C2C12 myoblasts. Granules also contained phosphorylated transactive response DNA-binding protein 43, ubiquitin, microtubule-associated protein 1A/1B light chains 3, and lysosome-associated membrane protein 2. Mutant VCP produced more T-intracellular antigen-1-positive granules than wild-type in the postarsenite exposure period. Similar results were observed for other granule components, indicating that mutant VCP delayed clearance of stress granules. Furthermore, stress granule resolution was impaired on differentiated C2C12 cells expressing mutant VCP. To address whether mutant VCP triggers dysregulation of the stress granule pathway invivo, we analyzed skeletal muscle of aged VCPR155H-knockin mice. We found significant increments in oxidated proteins but observed the stress granule markers RasGAP SH3-binding protein and phosphorylated eukaryotic translation initiation factor 2α unchanged. The mixed results indicate that mutant VCP together with aging lead to higher oxidative stress in skeletal muscle but were insufficient to disrupt the stress granule pathway. Our findings support that deficiencies in recovery from stressors may result in attenuated tolerance to stress that could trigger muscle degeneration.
Highlights
From the Molecular and Cell Biology,* School of Natural Sciences, University of California, Merced; and the Department of Pediatrics,y Division of Genetics and Genomics Medicine, University of California Irvine, Irvine, California
Stress granules were identified by staining with T-intracellular antigen-1 (TiA-1), an RNA binding protein presented in stress granules.[23]
We examined whether transactive response DNAbinding protein 43 (TDP-43) and phosphorylated TDP-43 were incorporated and aggregated in these stress granules, because aberrant cytoplasmic inclusions of TDP-43 are commonly observed in skeletal muscle tissue of IBMPFD
Summary
Valosin-containing protein (VCP) mutations cause inclusion body myopathy with Paget disease and frontotemporal dementia. The mixed results indicate that mutant VCP together with aging lead to higher oxidative stress in skeletal muscle but were insufficient to disrupt the stress granule pathway. Progressive muscle wasting affects respiratory muscles and the heart, leading to respiratory and cardiac failures, which are the main cause of death in these patients.[5] At the cellular level, pathologic hallmarks include rimmed vacuoles positive for microtubule-associated protein 1A/1Blight chain 3 (LC3),[6] abnormal buildup of ubiquitylated proteins, and mislocalization of transactive response DNAbinding protein 43 (TDP-43) to the cytoplasmic compartment in muscle fibers.[7,8] Interestingly, distribution of VCP appears unaltered in affected cells.[9].
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