TY - JOUR A1 - Reeg, Sandra A1 - Jung, Tobias A1 - Castro, José Pedro A1 - Davies, Kelvin J. A. A1 - Henze, Andrea A1 - Grune, Tilman T1 - The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. In order to prevent aggregation of oxidized proteins, cells recur to the 20S proteasome, an efficient turnover proteolysis complex. It has previously been shown that upon oxidative stress the 26S proteasome, another form, dissociates into the 20S form. A critical player implicated in its dissociation is the Heat Shock Protein 70 (Hsp70), which promotes an increase in free 20S proteasome and, therefore, an increased capability to degrade oxidized proteins. The aim of this study was to test whether or not Hsp70 is involved in cooperating with the 20S proteasome for a selective degradation of oxidatively damaged proteins. Our results demonstrate that Hsp70 expression is induced in HT22 cells as a result of mild oxidative stress conditions. Furthermore, Hsp70 prevents the accumulation of oxidized proteins and directly promotes their degradation by the 20S proteasome. In contrast the expression of the Heat shock cognate protein 70 (Hsc70) was not changed in recovery after oxidative stress and Hsc70 has no influence on the removal of oxidatively damaged proteins. We were able to demonstrate in HT22 cells, in brain homogenates from 129/SV mice and in vitro, that there is an increased interaction of Hsp70 with oxidized proteins, but also with the 20S proteasome, indicating a role of Hsp70 in mediating the interaction of oxidized proteins with the 20S proteasome. Thus, our data clearly implicate an involvement of Hsp70 oxidatively damaged protein degradation by the 20S proteasome. c) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). KW - Protein oxidation KW - Proteasome KW - Chaperone KW - HSP70 Y1 - 2016 U6 - https://doi.org/10.1016/j.freeradbiomed.2016.08.002 SN - 0891-5849 SN - 1873-4596 VL - 99 SP - 153 EP - 166 PB - Elsevier CY - New York ER - TY - JOUR A1 - John, Cathleen A1 - Grune, Jana A1 - Ott, Christiane A1 - Nowotny, Kerstin A1 - Deubel, Stefanie A1 - Kühne, Arne A1 - Schubert, Carola A1 - Kintscher, Ulrich A1 - Regitz-Zagrosek, Vera A1 - Grune, Tilman T1 - Sex Differences in Cardiac Mitochondria in the New Zealand Obese Mouse JF - Frontiers in Endocrinology N2 - Background: Obesity is a risk factor for diseases including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. Diabetes itself contributes to cardiac damage. Thus, studying cardiovascular events and establishing therapeutic intervention in the period of type T2DM onset and manifestation are of highest importance. Mitochondrial dysfunction is one of the pathophysiological mechanisms leading to impaired cardiac function. Methods: An adequate animal model for studying pathophysiology of T2DM is the New Zealand Obese (NZO) mouse. These mice were maintained on a high-fat diet (HFD) without carbohydrates for 13 weeks followed by 4 week HFD with carbohydrates. NZO mice developed severe obesity and only male mice developed manifest T2DM. We determined cardiac phenotypes and mitochondrial function as well as cardiomyocyte signaling in this model. Results: The development of an obese phenotype and T2DM in male mice was accompanied by an impaired systolic function as judged by echocardiography and MyH6/7 expression. Moreover, the mitochondrial function only in male NZO hearts was significantly reduced and ERK1/2 and AMPK protein levels were altered. Conclusions: This is the first report demonstrating that the cardiac phenotype in male diabetic NZO mice is associated with impaired cardiac energy function and signaling events. KW - NZO KW - heart KW - obesity KW - mitochondrial function KW - echocardiography KW - systolic function Y1 - 2018 U6 - https://doi.org/10.3389/fendo.2018.00732 SN - 1664-2392 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Speckmann, Bodo A1 - Schulz, Sarah A1 - Hiller, Franziska A1 - Hesse, Deike A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Geisel, Juergen A1 - Obeid, Rima A1 - Grune, Tilman A1 - Kipp, Anna Patricia T1 - Selenium increases hepatic DNA methylation and modulates one-carbon metabolism in the liver of mice JF - The journal of nutritional biochemistry N2 - The average intake of the essential trace element selenium (Se) is below the recommendation in most European countries, possibly causing sub-optimal expression of selenoproteins. It is still unclear how a suboptimal Se status may affect health. To mimic this situation, mice were fed one of three physiologically relevant amounts of Se. We focused on the liver, the organ most sensitive to changes in the Se supply indicated by hepatic glutathione peroxidase activity. In addition, liver is the main organ for synthesis of methyl groups and glutathione via one-carbon metabolism. Accordingly, the impact of Se on global DNA methylation, methylation capacity, and gene expression was assessed. We observed higher global DNA methylation indicated by LINE1 methylation, and an increase of the methylation potential as indicated by higher S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio and by elevated mRNA expression of serine hydroxymethyltransferase in both or either of the Se groups. Furthermore, increasing the Se supply resulted in higher plasma concentrations of triglycerides. Hepatic expression of glycolytic and lipogenic genes revealed consistent Se dependent up-regulation of glucokinase. The sterol regulatory element-binding transcription factor 1 (Srebf1) was also up-regulated by Se. Both effects were confirmed in primary hepatocytes. In contrast to the overall Se-dependent increase of methylation capacity, the up-regulation of Srebf1 expression was paralleled by reduced local methylation of a specific CpG site within the Srebf1 gene. Thus, we provided evidence that Se-dependent effects on lipogenesis involve epigenetic mechanisms. (C) 2017 The Authors. Published by Elsevier Inc. KW - Selenium KW - DNA methylation KW - Liver KW - Lipogenesis KW - Srebf1 Y1 - 2017 U6 - https://doi.org/10.1016/j.jnutbio.2017.07.002 SN - 0955-2863 SN - 1873-4847 VL - 48 SP - 112 EP - 119 PB - Elsevier CY - New York ER - TY - JOUR A1 - Wiedmer, Petra A1 - Jung, Tobias A1 - Castro, Jose Pedro A1 - Pomatto, Laura C. D. A1 - Sun, Patrick Y. A1 - Davies, Kelvin J. A. A1 - Grune, Tilman T1 - Sarcopenia BT - molecular mechanisms and open questions JF - Ageing research reviews : ARR N2 - Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality.
Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function.
In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions. KW - molecular pathways KW - proteostasis KW - proteasome KW - autophagy KW - mitochondria, KW - muscle fibre composition Y1 - 2020 U6 - https://doi.org/10.1016/j.arr.2020.101200 SN - 1568-1637 SN - 1872-9649 VL - 65 PB - Elsevier CY - Clare ER - TY - JOUR A1 - Kessler, Katharina A1 - Hornemann, Silke A1 - Rudovich, Natalia A1 - Weber, Daniela A1 - Grune, Tilman A1 - Kramer, Achim A1 - Pfeiffer, Andreas F. H. A1 - Pivovarova-Ramich, Olga T1 - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers JF - Nutrients N2 - Meal timing affects metabolic regulation in humans. Most studies use blood samples fortheir investigations. Saliva, although easily available and non-invasive, seems to be rarely used forchrononutritional studies. In this pilot study, we tested if saliva samples could be used to studythe effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated salivasamples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones andinflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports inblood and showing significant correlations with blood levels. The rhythm patterns were similar forboth diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolicand inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for thenon-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies. KW - meal timing KW - saliva KW - circadian clock KW - adiponectin KW - resistin KW - visfatin KW - insulin KW - melatonin KW - cortisol KW - cytokines Y1 - 2020 U6 - https://doi.org/10.3390/nu12020340 SN - 2072-6643 IS - 2 SP - 1 EP - 12 PB - MDPI CY - Basel ER - TY - JOUR A1 - Kehm, Richard A1 - Jähnert, Markus A1 - Deubel, Stefanie A1 - Flore, Tanina A1 - König, Jeannette A1 - Jung, Tobias A1 - Stadion, Mandy A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Grune, Tilman A1 - Höhn, Annika T1 - Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP) JF - Redox Biology N2 - Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice. KW - aging KW - redox homeostasis KW - metabolic stress KW - beta-cells KW - cell cycle KW - thioredoxin-interacting protein Y1 - 2020 U6 - https://doi.org/10.1016/j.redox.2020.101748 SN - 2213-2317 VL - 37 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Raupbach, Jana A1 - Ott, Christiane A1 - König, Jeannette A1 - Grune, Tilman T1 - Proteasomal degradation of glycated proteins depends on substrate unfolding: Preferred degradation of moderately modified myoglobin JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - The Maillard reaction generates protein modifications which can accumulate during hyperglycemia or aging and may have inflammatory consequences. The proteasome is one of the major intracellular systems involved in the proteolytic degradation of modified proteins but its role in the degradation of glycated proteins is scarcely studied. In this study, chemical and structural changes of glycated myoglobin were analyzed and its degradation by 20S proteasome was studied. Myoglobin was incubated with physiological (5-10 mM), moderate (50-100 mM) and severe levels (300 mM) of glucose or methylglyoxal (MGO, 50 mM). Glycation increased myoglobin's fluorescence and surface hydrophobicity. Severe glycation generated crosslinked proteins as shown by gel electrophoresis. The concentration of advanced glycation endproducts (AGEs) N-epsilon-carboxymethyl lysine (CML), N-epsilon-carboxyethyl lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), pentosidine and pyrraline was analyzed after enzymatic hydrolysis followed by UPLC-MS/MS. Higher concentrations of glucose increased all analyzed AGEs and incubation with MGO led to a pronounced increase of CEL and MG-H1. The binding of the heme group to apo-myoglobin was decreased with increasing glycation indicating the loss of tertiary protein structure. Proteasomal degradation of modified myoglobin compared to native myoglobin depends on the degree of glycation: physiological conditions decreased proteasomal degradation whereas moderate glycation increased degradation. Severe glycation again decreased proteolytic cleavage which might be due to crosslinking of protein monomers. The activity of the proteasomal subunit beta 5 is influenced by the presence of glycated myoglobin. In conclusion, the role of the proteasome in the degradation of glycated proteins is highly dependent on the level of glycation and consequent protein unfolding. KW - Glycation KW - Myoglobin KW - Heme KW - Advanced glycation endproducts KW - 20S KW - proteasome Y1 - 2020 U6 - https://doi.org/10.1016/j.freeradbiomed.2019.11.024 SN - 0891-5849 SN - 1873-4596 VL - 152 SP - 516 EP - 524 PB - Elsevier CY - New York ER - TY - JOUR A1 - Henning, Thorsten A1 - Kochlik, Bastian Max A1 - Kusch, Paula A1 - Strauss, Matthias A1 - Juric, Viktorija A1 - Pignitter, Marc A1 - Marusch, Frank A1 - Grune, Tilman A1 - Weber, Daniela T1 - Pre-Operative assessment of micronutrients, amino acids, phospholipids and oxidative stress in bariatric surgery candidates JF - Antioxidants : open access journal N2 - Obesity has been linked to lower concentrations of fat-soluble micronutrients and higher concentrations of oxidative stress markers as well as an altered metabolism of branched chain amino acids and phospholipids. In the context of morbid obesity, the aim of this study was to investigate whether and to which extent plasma status of micronutrients, amino acids, phospholipids and oxidative stress differs between morbidly obese (n = 23) and non-obese patients (n = 13). In addition to plasma, malondialdehyde, retinol, cholesterol and triglycerides were assessed in visceral and subcutaneous adipose tissue in both groups. Plasma gamma-tocopherol was significantly lower (p < 0.011) in the obese group while other fat-soluble micronutrients showed no statistically significant differences between both groups. Branched-chain amino acids (all p < 0.008) and lysine (p < 0.006) were significantly higher in morbidly obese patients compared to the control group. Malondialdehyde concentrations in both visceral (p < 0.016) and subcutaneous (p < 0.002) adipose tissue were significantly higher in the morbidly obese group while plasma markers of oxidative stress showed no significant differences between both groups. Significantly lower plasma concentrations of phosphatidylcholine, phosphatidylethanolamine, lyso-phosphatidylethanolamine (all p < 0.05) and their corresponding ether-linked analogs were observed, which were all reduced in obese participants compared to the control group. Pre-operative assessment of micronutrients in patients undergoing bariatric surgery is recommended for early identification of patients who might be at higher risk to develop a severe micronutrient deficiency post-surgery. Assessment of plasma BCAAs and phospholipids in obese patients might help to differentiate between metabolic healthy patients and those with metabolic disorders. KW - obesity KW - micronutrients KW - oxidative stress KW - amino acids KW - phospholipids KW - vitamins KW - plasma Y1 - 2022 U6 - https://doi.org/10.3390/antiox11040774 SN - 2076-3921 VL - 11 IS - 4 PB - MDPI CY - Basel ER - TY - JOUR A1 - Weber, Daniela A1 - Kochlik, Bastian Max A1 - Demuth, Ilja A1 - Steinhagen-Thiessen, Elisabeth A1 - Grune, Tilman A1 - Norman, Kristina T1 - Plasma carotenoids, tocopherols and retinol BT - Association with age in the Berlin Aging Study II JF - Redox Biology N2 - Regular consumption of fruits and vegetables, which is related to high plasma levels of lipid-soluble micro-nutrients such as carotenoids and tocopherols, is linked to lower incidences of various age-related diseases. Differences in lipid-soluble micronutrient blood concentrations seem to be associated with age. Our retrospective analysis included men and women aged 22-37 and 60-85 years from the Berlin Aging Study II. Participants with simultaneously available plasma samples and dietary data were included (n = 1973). Differences between young and old groups were found for plasma lycopene, alpha-carotene, alpha-tocopherol, beta-cryptoxanthin (only in women), and gamma-tocopherol (only in men). beta-Carotene, retinol and lutein/zeaxanthin did not differ between young and old participants regardless of the sex. We found significant associations for lycopene, alpha-carotene (both inverse), alpha-tocopherol, gamma-tocopherol, and beta-carotene (all positive) with age. Adjusting for BMI, smoking status, season, cholesterol and dietary intake confirmed these associations, except for beta-carotene. These micronutrients are important antioxidants and associated with lower incidence of age-related diseases, therefore it is important to understand the underlying mechanisms in order to implement dietary strategies for the prevention of age-related diseases. To explain the lower lycopene and alpha-carotene concentration in older subjects, bioavailability studies in older participants are necessary. KW - carotenoids KW - tocopherols KW - micronutrients KW - age KW - plasma KW - food frequency questionnaire Y1 - 2020 U6 - https://doi.org/10.1016/j.redox.2020.101461 SN - 2213-2317 VL - 32 SP - 1 EP - 8 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Grune, Tilman T1 - Oxidized protein aggregates BT - formation and biological effects JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - The study of protein aggregates has a long history. While in the first decades until the 80ies of the 20th century only the observation of the presence of such aggregates was reported, later the biochemistry of the formation and the biological effects of theses aggregates were described. This review focusses on the complexity of the biological effects of protein aggregates and its potential role in the aging process. Y1 - 2020 U6 - https://doi.org/10.1016/j.freeradbiomed.2020.02.014 SN - 0891-5849 SN - 1873-4596 VL - 150 SP - 120 EP - 124 PB - Elsevier CY - New York ER -