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1.
Exercise training results in depot-specific adaptations to adipose tissue mitochondrial function.
Mendham, AE, Larsen, S, George, C, Adams, K, Hauksson, J, Olsson, T, Fortuin-de Smidt, MC, Nono Nankam, PA, Hakim, O, Goff, LM, et al
Scientific reports. 2020;(1):3785
Abstract
We assessed differences in mitochondrial function in gluteal (gSAT) and abdominal subcutaneous adipose tissue (aSAT) at baseline and in response to 12-weeks of exercise training; and examined depot-specific associations with body fat distribution and insulin sensitivity (SI). Obese, black South African women (n = 45) were randomized into exercise (n = 23) or control (n = 22) groups. Exercise group completed 12-weeks of aerobic and resistance training (n = 20), while the control group (n = 15) continued usual behaviours. Mitochondrial function (high-resolution respirometry and fluorometry) in gSAT and aSAT, SI (frequently sampled intravenous glucose tolerance test), body composition (dual-energy X-ray absorptiometry), and ectopic fat (MRI) were assessed pre- and post-intervention. At baseline, gSAT had higher mitochondrial respiratory capacity and hydrogen peroxide (H2O2) production than aSAT (p < 0.05). Higher gSAT respiration was associated with higher gynoid fat (p < 0.05). Higher gSAT H2O2 production and lower aSAT mitochondrial respiration were independently associated with lower SI (p < 0.05). In response to training, SI improved and gynoid fat decreased (p < 0.05), while H2O2 production reduced in both depots, and mtDNA decreased in gSAT (p < 0.05). Mitochondrial respiration increased in aSAT and correlated with a decrease in body fat and an increase in soleus and hepatic fat content (p < 0.05). This study highlights the importance of understanding the differences in mitochondrial function in multiple SAT depots when investigating the pathophysiology of insulin resistance and associated risk factors such as body fat distribution and ectopic lipid deposition. Furthermore, we highlight the benefits of exercise training in stimulating positive adaptations in mitochondrial function in gluteal and abdominal SAT depots.
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Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.
Wang, Y, Hernandez, G, Mack, WJ, Schneider, LS, Yin, F, Brinton, RD
Menopause (New York, N.Y.). 2020;(1):57-65
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Abstract
OBJECTIVE PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.
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A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo.
Berk, M, Turner, A, Malhi, GS, Ng, CH, Cotton, SM, Dodd, S, Samuni, Y, Tanious, M, McAulay, C, Dowling, N, et al
BMC medicine. 2019;(1):18
Abstract
BACKGROUND A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis. METHODS A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes. RESULTS One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group. CONCLUSIONS These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction. TRIAL REGISTRATION ANZCTR ( ACTRN12612000830897 ).
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Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance.
Kenny, HC, Rudwill, F, Breen, L, Salanova, M, Blottner, D, Heise, T, Heer, M, Blanc, S, O'Gorman, DJ
Diabetologia. 2017;(8):1491-1501
Abstract
AIMS/HYPOTHESIS Physical inactivity has broad implications for human disease including insulin resistance, sarcopenia and obesity. The present study tested the hypothesis that (1) impaired mitochondrial respiration is linked with blunted insulin sensitivity and loss of muscle mass in healthy young men, and (2) resistive vibration exercise (RVE) would mitigate the negative metabolic effects of bed rest. METHODS Participants (n = 9) were maintained in energy balance during 21 days of bed rest with RVE and without (CON) in a crossover study. Mitochondrial respiration was determined by high-resolution respirometry in permeabilised fibre bundles from biopsies of the vastus lateralis. A hyperinsulinaemic-euglycaemic clamp was used to determine insulin sensitivity, and body composition was assessed by dual-energy x-ray absorptiometry (DEXA). RESULTS Body mass (-3.2 ± 0.5 kg vs -2.8 ± 0.4 kg for CON and RVE, respectively, p < 0.05), fat-free mass (-2.9 ± 0.5 kg vs -2.7 ± 0.5 kg, p < 0.05) and peak oxygen consumption ([Formula: see text]) (10-15%, p < 0.05) were all reduced following bed rest. Bed rest decreased insulin sensitivity in the CON group (0.04 ± 0.002 mg kgFFM-1 [pmol l-1] min-1 vs 0.03 ± 0.002 mg kgFFM-1 [pmol l-1] min-1 for baseline vs post-CON), while RVE mitigated this response (0.04 ± 0.003 mg kgFFM-1 [pmol l-1] min-1). Mitochondrial respiration (oxidative phosphorylation and electron transport system capacity) decreased in the CON group but not in the RVE group when expressed relative to tissue weight but not when normalised for citrate synthase activity. LEAK respiration, indicating a decrease in mitochondrial uncoupling, was the only component to remain significantly lower in the CON group after normalisation for citrate synthase. This was accompanied by a significant decrease in adenine nucleotide translocase protein content. CONCLUSIONS/INTERPRETATION Reductions in muscle mitochondrial respiration occur concomitantly with insulin resistance and loss of muscle mass during bed rest and may play a role in the adaptations to physical inactivity. Significantly, we show that RVE is an effective strategy to partially prevent some of the deleterious metabolic effects of bed rest.
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Lean-seafood intake decreases urinary markers of mitochondrial lipid and energy metabolism in healthy subjects: Metabolomics results from a randomized crossover intervention study.
Schmedes, M, Aadland, EK, Sundekilde, UK, Jacques, H, Lavigne, C, Graff, IE, Eng, Ø, Holthe, A, Mellgren, G, Young, JF, et al
Molecular nutrition & food research. 2016;(7):1661-72
Abstract
SCOPE Proteins constitute an important part of the human diet, but understanding of the effects of different dietary protein sources on human metabolism is sparse. We aimed to elucidate diet-induced metabolic changes through untargeted urinary metabolomics after four weeks of intervention with lean-seafood or nonseafood diets. It is shown that lean-seafood intake reduces urinary excretion of metabolites involved in mitochondrial lipid and energy metabolism possibly facilitating a higher lipid catabolism in healthy subjects. METHODS In a randomized controlled trial with crossover design, 20 healthy subjects consumed two balanced diets that varied in main protein sources for 4 weeks. Morning spot urine samples were collected before and after each intervention period. Untargeted metabolomics based on (1) H NMR spectroscopy and LC-MS analyses were applied to characterize the urinary metabolic response to the interventions. RESULTS The lean-seafood diet period reduced the urinary level of l-carnitine, 2,6-dimethylheptanoylcarnitine, and N-methyl-2-pyridone-5-carboxamide, relative to the nonseafood period. The dietary analysis revealed that the higher urinary level of trimethylamine-N-oxide after the lean-seafood diet period and guanidinoacetate and 3-methylhistidine after the nonseafood diet period was related to the endogenous content of these compounds in the diets. CONCLUSIONS Our data reveal that 4 weeks of lean-seafood intake reduces urinary excretion of metabolites involved in mitochondrial lipid and energy metabolism possibly facilitating a higher lipid catabolism in healthy subjects after the lean-seafood intake.
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Exercise Training Alleviates Hypoxia-induced Mitochondrial Dysfunction in the Lymphocytes of Sedentary Males.
Tsai, HH, Chang, SC, Chou, CH, Weng, TP, Hsu, CC, Wang, JS
Scientific reports. 2016;:35170
Abstract
This study elucidates how interval and continuous exercise regimens affect the mitochondrial functionality of lymphocytes under hypoxic stress. Sixty healthy sedentary males were randomly assigned to engage in either high-intensity interval training (HIIT, 3 min intervals at 80% and 40% VO2max, n = 20) or moderate-intensity continuous training (MICT, sustained 60% VO2max, n = 20) for 30 min/day, 5 days/week for 6 weeks or were assigned to a control group that did not receive exercise intervention (n = 20). Lymphocyte phenotypes/mitochondrial functionality under hypoxic exercise (HE, 100 W under 12% O2) were determined before and after the various interventions. Before the intervention, HE (i) increased the mobilization of senescent (CD57+/CD28-) lymphocytes into the blood, (ii) decreased the ATP-linked O2 consumption rate (OCR), the reserve capacity of OCR, and the citrate synthase activity in the mitochondria, and (iii) lowered the mitochondrial membrane potential (MP) and elevated the matrix oxidant burden (MOB) of lymphocytes. However, both HIIT and MICT significantly (i) decreased blood senescent lymphocyte counts, (ii) enhanced the mitochondrial OCR with increased citrate synthase and succinate dehydrogenase activities, (iii) increased mitochondrial MP and decreased MOB and (iv) increased the ratio of mitofusin to DRP-1 in lymphocytes after HE. Thus, we concluded that either HIIT or MICT effectively improves lymphocyte mitochondrial functionality by enhancing oxidative phosphorylation and suppressing oxidative damage under hypoxic conditions.
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Diet supplementation with DHA-enriched food in football players during training season enhances the mitochondrial antioxidant capabilities in blood mononuclear cells.
Capó, X, Martorell, M, Sureda, A, Llompart, I, Tur, JA, Pons, A
European journal of nutrition. 2015;(1):35-49
Abstract
PURPOSE Exercise induces oxidative stress and causes adaptations in antioxidant defenses. The aim of the present study was to determine the effects of a 2-month diet supplementation with docosahexaenoic acid (DHA) on the pro-oxidant and antioxidant status of peripheral blood mononuclear cells (PBMCs) during football training and after acute exercise. METHODS Fifteen male football players, in a randomized double-blind trial, ingested a beverage enriched with DHA or a placebo for 8 weeks. Blood samples were collected in basal conditions before and after the training period and after an acute and intense exercise. RESULTS The training season increased the carbonyl and nitrotyrosine index but decreased the malondialdehyde (MDA) levels. Basal catalase activity decreased in both groups after 8 weeks of training, whereas glutathione peroxidase activity increased mainly in the placebo group. Protein levels of uncoupling proteins (UCP2 and UCP3) and inducible nitric oxide synthase significantly increased after the training period. Acute exercise induced redistribution in the number of circulating cells, increased the MDA levels and nitrotyrosine index, and decreased the levels of nitrate. Acute exercise also increased PBMCs reactive oxygen species (ROS) production after immune stimulation. Diet supplementation with DHA significantly increased the UCP3 levels after training and the superoxide dismutase protein levels after acute exercise, and reduced the production of ROS after acute exercise. CONCLUSION Docosahexaenoic acid increased the antioxidant capabilities while reducing the mitochondrial ROS production in a regular football training period and reduced the oxidative damage markers in response to acute exercise.
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Dietary inorganic nitrate improves mitochondrial efficiency in humans.
Larsen, FJ, Schiffer, TA, Borniquel, S, Sahlin, K, Ekblom, B, Lundberg, JO, Weitzberg, E
Cell metabolism. 2011;(2):149-59
Abstract
Nitrate, an inorganic anion abundant in vegetables, is converted in vivo to bioactive nitrogen oxides including NO. We recently demonstrated that dietary nitrate reduces oxygen cost during physical exercise, but the mechanism remains unknown. In a double-blind crossover trial we studied the effects of a dietary intervention with inorganic nitrate on basal mitochondrial function and whole-body oxygen consumption in healthy volunteers. Skeletal muscle mitochondria harvested after nitrate supplementation displayed an improvement in oxidative phosphorylation efficiency (P/O ratio) and a decrease in state 4 respiration with and without atractyloside and respiration without adenylates. The improved mitochondrial P/O ratio correlated to the reduction in oxygen cost during exercise. Mechanistically, nitrate reduced the expression of ATP/ADP translocase, a protein involved in proton conductance. We conclude that dietary nitrate has profound effects on basal mitochondrial function. These findings may have implications for exercise physiology- and lifestyle-related disorders that involve dysfunctional mitochondria.
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[Evaluation of an antioxidant and mitochondria-stimulating cream formula on the skin of patients with stable common vitiligo].
Rojas-Urdaneta, JE, Poleo-Romero, AG
Investigacion clinica. 2007;(1):21-31
Abstract
Vitiligo is a chronic illness of a yet unknown etiology, characterized by an acquired and progressive depigmentation of the skin. There are diverse treatments for this condition around the world, but up to now, none has been completely effective. The objective of this work was to evaluate the application of an antioxidant and mitochondrial stimulating formula, of topic use in leukodermic areas of patients with stable vulgar vitiligo. A clinical, experimental, randomized, double blind study was carried out in 50 male and 50 female patients with stable vulgar vitiligo. The patients were distributed in five groups as follows: Group 1 (labelled as VitilVenz AF): application of antioxidant and mitochondrial stimulating cream and oral administration of antioxidants and phenylalanine. Group 2 (labelled as Placebo AF): application of a placebo cream and oral administration of antioxidants and phenylalanine. Group 3 (labelled as without cream AF): oral administration of antioxidants and phenylalanine. Group 4 (labelled as Placebo cream): application of a placebo cream. Group 5 (labelled as VitilVenz): application of the antioxidant and mitochondrial stimulating cream. The following were measured in all patients: the clinical area of newly formed pigment every 30 days, during five months; and the presence of melanocytes in the histological study, at the beginning and at the end of treatment. The test of multiple comparison of Turkey-Kramer was used for the analysis of the results. The scheme of treatment that produced the best results was that of the Group 1, which consisted of the joint application of the antioxidant and mitochondrial stimulating cream and oral administration of antioxidants and phenylalanine (p < 0.001); followed by Group 5 that only received the topical treatment with the antioxidant and mitochondrial stimulating cream. The clinical and histological responses of these two groups (1 and 5) were significantly different to the rest of the groups. We concluded that the melanocytes in these patients could be in a dysfunctional state, product of the formation of free radicals that cause cellular and mitochondrial toxicity; and that these free radicals are removed by the antioxidant and mitochondrial stimulating elements present in the cream, turning the melanocytes functional and producing melanin in the achromic area of the vitiligo. This effect would be potentiated by the use of oral antioxidants and phenylalanine.
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Postprandial insulin response and mitochondrial oxidation in obese men nutritionally treated to lose weight.
Parra, MD, Martínez de Morentin, BE, Martínez, JA
European journal of clinical nutrition. 2005;(3):334-40
Abstract
Obesity, hyperglycemia, and insulin resistance have been associated to an oxidative mitochondrial dysfunction. The aim of this research was to evaluate the relation between carbohydrate metabolism and mitochondrial oxidation, as affected by the weight status and the weight loss induced by a calorie-restricted diet. Lean control men (BMI<25 kg/m2, n = 6) and obese men (BMI>30 kg/m2, n = 14), who were characterized as insulin resistant (n = 6) or insulin sensitive (n = 8) based on HOMA index values, participated in the trial. Plasma insulin levels and mitochondrial oxidation estimated by the 2-keto(1-13C)isocaproate breath test, were measured after ingestion of a test meal during 3 h. Obese subjects repeated the breath test protocol after a 10-week caloric restriction diet to lose weight. Postprandial insulin secretion tended to be marginally higher (P = 0.059) in both obese groups than in controls, while the rate of postprandial mitochondrial oxidation was markedly decreased (P = 0.019) in the obese subjects as compared with lean individuals. The nutritionally induced weight loss produced a rise in the postprandial oxidative process in volunteers initially considered as insulin resistant (P = 0.036), while no statistical differences in the insulin-sensitive obese (P = 0.241) were found. Interestingly, the percentage of oxidized tracer was inversely related to postprandial insulin secretion (r = -0.56; P = 0.001). In conclusion, these results support the hypothetized relation between carbohydrate metabolism and mitochondrial oxidation at a postprandial state in obese subjects, raising interest about mitochondria stimulation as a target in the therapy of obesity.