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 shockdactivated stress responses evident by T-intracellular antigen-1epositive 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-1epositive granules than wildtype 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 in vivo, we analyzed skeletal muscle of aged VCP R155H -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 2a 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. (Am J Pathol 2016 http://dx

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Diabetic hearts are in great risk of increased oxidant production from sustained elevations of glucose through activation of several pathways. One of the major sources of oxidant production within the cell are mitochondria through substrate metabolism. Oxidation of mitochondrial enzymes may impair their function resulting in accumulation of intermediates and reverse electron transfer which contributes to mitochondrial dysfunction. Glutathione (GSH) is the most abundant antioxidant in the body which with the aid of peroxidases is able to reduce cellular oxidants through electron donation. Transcription factor nuclear factor erythriod‐2‐related factor 2 (Nrf2) induces expression of antioxidant genes including those responsible for GSH synthesis. Nrf2 translocation serves as a defensive mechanism when oxidant production increases in the cytosol. We hypothesized that an elevation in plasma glucose facilitates Nrf2 nuclear translocation and subsequent expression of Nrf2‐associated genes. To address this hypothesis, an oral glucose tolerance test (oGTT) was performed in four groups (n = 6–8/group) of rats: 1) LETO (lean strain‐control), 2) vehicle‐treated, IR obese OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d), and 4) OLETF + angiotensin receptor blocker (ARB‐r). ARB normalized systolic blood pressure to control levels, while ARB‐r matched OLETF at 155±2.36 mmHg. Baseline GSH levels were maintained over 360 min post‐glucose administration in LETO, but GSH levels increased 125% in OLETF. While ARB had no detectable effect on GSH levels, GSH levels increased 52% in ARB‐r compared to LETO. Removal of ARB treatment may be more beneficial than long term ARB treatment. However, our data suggest that acute increases in glucose can increase GSH levels in the early phases of diabetic cardiomyopathy liking to protect against the potential for increased oxidant production.

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