ABSTRACT
Statins are prescribed for the treatment of elevated cholesterol, but they may negatively affect metabolism, muscle performance, and the response to training. Coenzyme Q10 (CoQ10) supplementation may alleviate these effects. Combined simvastatin and CoQ10 treatment during physical training has never been tested. We studied the response to 8 weeks training (maximal oxygen uptake ( VÌO2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ ), fat oxidation (MFO), the workload at which MFO occurred, and muscle strength) in statin naive dyslipidaemic patients who received simvastatin (40 mg/day) with (S + Q, n = 9) or without (S + Pl, n = 10) CoQ10 supplementation (2 × 200 mg/day) or placebo (Pl + Pl, n = 7) in a randomized, double-blind placebo-controlled study. VÌO2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ and maximal workload increased with training (main effect of time, P < 0.05). MFO increased from 0.29 ± 0.10, 0.26 ± 0.10, and 0.38 ± 0.09 to 0.42 ± 0.09, 0.38 ± 0.10 and 0.48 ± 0.16 g/min in S + Q, S + Pl, and Pl + Pl, respectively (main effect of time, P = 0.0013). The workload at MFO increased from 75 ± 25, 56 ± 23, and 72 ± 17 to 106 ± 25, 84 ± 13 and 102 ± 31 W in S + Q, S + Pl, and Pl + Pl, respectively (main effect of time, P < 0.0001). Maximal voluntary contraction and rate of force development were unchanged. Exercise improved aerobic physical capacity and simvastatin with or without CoQ10 supplementation did not inhibit this adaptation. The similar increases in MFO and in the workload at which MFO occurred in response to training shows that the ability to adapt substrate selection and oxidation rates is preserved with simvastatin treatment, despite the potential negative impact of simvastatin at the mitochondrial level. CoQ10 supplementation does not augment this adaptation. KEY POINTS: Simvastatins are prescribed for treatment of elevated cholesterol, but they may negatively affect metabolism, muscle performance and the response to training. Coenzyme Q10 (CoQ10) supplementation may alleviate some of these effects. We found that simvastatin treatment does not negatively affect training-induced adaptations of substrate oxidation during exercise. Likewise, maximal oxygen uptake increases with physical training also in patients in treatment with simvastatin. CoQ10 supplementation in simvastatin-treated patients presents no advantage in the adaptations to physical training Simvastatin treatment decreases plasma concentrations of total CoQ10, but this can be alleviated by simultaneous supplementation with CoQ10.
Subject(s)
Simvastatin , Ubiquinone , Dietary Supplements , Exercise/physiology , Humans , Muscles , Simvastatin/pharmacology , Simvastatin/therapeutic use , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacologyABSTRACT
Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide to NAD+. As low hepatic NAD+ levels have been linked to the development of nonalcoholic fatty liver disease, we hypothesized that ablation of hepatic Nampt would affect susceptibility to liver injury in response to diet-induced metabolic stress. Following 3 weeks on a low-methionine and choline-free 60% high-fat diet, hepatocyte-specific Nampt knockout (HNKO) mice accumulated less triglyceride than WT littermates but had increased histological scores for liver inflammation, necrosis, and fibrosis. Surprisingly, liver injury was also observed in HNKO mice on the purified control diet. This HNKO phenotype was associated with decreased abundance of mitochondrial proteins, especially proteins involved in oxidoreductase activity. High-resolution respirometry revealed lower respiratory capacity in purified control diet-fed HNKO liver. In addition, fibrotic area in HNKO liver sections correlated negatively with hepatic NAD+, and liver injury was prevented by supplementation with NAD+ precursors nicotinamide riboside and nicotinic acid. MS-based proteomic analysis revealed that nicotinamide riboside supplementation rescued hepatic levels of oxidoreductase and OXPHOS proteins. Finally, single-nucleus RNA-Seq showed that transcriptional changes in the HNKO liver mainly occurred in hepatocytes, and changes in the hepatocyte transcriptome were associated with liver necrosis. In conclusion, HNKO livers have reduced respiratory capacity, decreased abundance of mitochondrial proteins, and are susceptible to fibrosis because of low NAD+ levels. Our data suggest a critical threshold level of hepatic NAD+ that determines the predisposition to liver injury and supports that NAD+ precursor supplementation can prevent liver injury and nonalcoholic fatty liver disease progression.
Subject(s)
Hepatocytes/metabolism , Mitochondria, Liver/metabolism , NAD/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Cytokines/deficiency , Cytokines/metabolism , Mice , Mice, Knockout , Mitochondria, Liver/genetics , NAD/genetics , Nicotinamide Phosphoribosyltransferase/deficiency , Nicotinamide Phosphoribosyltransferase/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Oxidative Phosphorylation , PhenotypeABSTRACT
The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000 mg GSH per day or placebo for 3 weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H2O2) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (â¼19%) in the GSH group; no change was seen in GSH to glutathione disulfide ratio. Skeletal muscle mitochondrial H2O2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine or the DNA oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty: Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without T2DM. H2O2 emission rate from skeletal muscle mitochondria was not affected by GSH supplementation.
Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Dietary Supplements , Glutathione/administration & dosage , Insulin Resistance/physiology , Obesity/physiopathology , Administration, Oral , Biomarkers/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Dietary Supplements/adverse effects , Glucose Tolerance Test , Glutathione/adverse effects , Glutathione/blood , Glutathione/metabolism , Glutathione Disulfide/metabolism , Humans , Hydrogen Peroxide/metabolism , Middle Aged , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Obesity/metabolism , Oxidative Stress , Oxygen ConsumptionABSTRACT
KEY POINTS: This is the first long-term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology. NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle. NR supplementation does not affect NAD metabolite concentrations in skeletal muscle. Respiration, distribution and quantity of muscle mitochondria are unaffected by NR. NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. ABSTRACT: Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD+ ) precursor nicotinamide riboside (NR) boosts NAD+ levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle-aged, obese, insulin-resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo-controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12 weeks. Skeletal muscle biopsies were collected before and after the intervention. Mitochondrial respiratory capacity was determined by high-resolution respirometry on single muscle fibres. Protein abundance and mRNA expression were measured by Western blot and quantitative PCR analyses, respectively, and in a subset of the participants (placebo n = 8; NR n = 8) we quantified mitochondrial fractional area and mitochondrial morphology by laser scanning confocal microscopy. Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD+ biosynthetic enzyme in skeletal muscle, decreased by 14% with NR. However, steady-state NAD+ levels as well as gene expression and protein abundance of other NAD+ biosynthetic enzymes remained unchanged. Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed. Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin-resistant men. Future studies on the effects of NR on human skeletal muscle may include both sexes and potentially provide comparisons between young and older people.
Subject(s)
Insulin Resistance , Mitochondria, Muscle/physiology , Muscle, Skeletal/physiology , Niacinamide/analogs & derivatives , Obesity/physiopathology , Humans , Male , Middle Aged , NAD/metabolism , Niacinamide/administration & dosage , Nicotinamide Phosphoribosyltransferase/metabolism , Pyridinium CompoundsABSTRACT
PURPOSE: Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and is known to be an inflammatory process. Statin therapy decreases both cholesterol and inflammation and is used in primary and secondary prevention of CVD. However, a statin induced decrease of plasma concentrations of the antioxidant coenzyme Q10 (CoQ10), may prevent the patients from reaching their optimal anti-inflammatory potential. Here, we studied the anti-inflammatory effect of Simvastatin therapy and CoQ10 supplementation. METHODS: 35 patients in primary prevention with Simvastatin (40â¯mg/day) were randomized to receive oral CoQ10 supplementation (400â¯mg/d) or placebo for 8â¯weeks. 20 patients with hypercholesterolemia who received no cholesterol-lowering treatment was a control group. Plasma concentrations of lipids and inflammatory biomarkers (interleukin-6 (IL6); -8 (IL8); -10 (IL10), tumor necrosis factor-α (TNFα); high-sensitivity C reactive protein (hsCRP)) as well as glycated hemoglobin (HbA1c) were quantified before and after the intervention. RESULTS: No significant change in inflammatory markers or lipids was observed after CoQ10 supplementation Patients in Simvastatin therapy had significantly (Pâ¯<â¯0.05) lower baseline concentration of IL6 (0.31⯱â¯0.03â¯pg/ml), IL8 (1.6⯱â¯0.1â¯pg/ml) IL10 (0.16⯱â¯0.02â¯pg/ml) and borderline (Pâ¯=â¯0.053) lower TNFα (0.88⯱â¯0.05â¯pg/ml), but not hsCRP (1.34⯱â¯0.19â¯mg/l) compared with the control group (0.62⯱â¯0.08, 2.6⯱â¯0.2, 0.25⯱â¯0.01, 1.07⯱â¯0.09, and 1.90⯱â¯0.35, respectively). CONCLUSIONS: Simvastatin therapy has beneficial effects on inflammatory markers in plasma, but CoQ10 supplementation seems to have no additional potentiating effect in patients in primary prevention. In contrast, glucose homeostasis may improve with CoQ10 supplementation.
Subject(s)
Atherosclerosis , C-Reactive Protein/metabolism , Cytokines/blood , Glycated Hemoglobin/metabolism , Simvastatin/administration & dosage , Ubiquinone/analogs & derivatives , Adult , Aged , Atherosclerosis/blood , Atherosclerosis/drug therapy , Biomarkers/blood , Double-Blind Method , Female , Humans , Inflammation/blood , Inflammation/drug therapy , Male , Middle Aged , Ubiquinone/administration & dosageABSTRACT
Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSBm/m) and C57Bl/6 (WT) controls and comparing young (2-5 months) to middle-aged mice (13-14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSBm/m hippocampus, but not in CSBm/m cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased with age. Notably, an inverse correlation between heterogeneity and CI was found in both genotypes, indicating that heterogeneity reflects mitochondrial dysfunction. The ratio between fission and fusion gene expression reflected age-related alterations in mitochondrial morphology but not heterogeneity. Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSBm/m compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event in brain aging.
Subject(s)
Aging/metabolism , Brain/metabolism , Cell Respiration , Electron Transport Complex I/metabolism , Frontal Lobe/metabolism , Hippocampus/metabolism , Mitochondria/metabolism , Mitochondrial Size , Animals , DNA Helicases , DNA Repair Enzymes , DNA, Mitochondrial/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Mice, Transgenic , Mitochondria/pathology , Poly-ADP-Ribose Binding Proteins , RNA, Messenger/metabolismABSTRACT
AIM: LIFESTAT is an interdisciplinary project that leverages approaches and knowledge from medicine, the humanities and the social sciences to analyze the impact of statin use on health, lifestyle and well-being in cohorts of Danish citizens. The impetus for the study is the fact that 10% of the population in the Scandinavian countries are treated with statins in order to maintain good health and to avoid cardiovascular disease by counteracting high blood levels of cholesterol. The potential benefit of treatment with statins should be considered in light of evidence that statin use has prevalent and unintended side effects (e.g. myalgia, and glucose and exercise intolerance). METHODS: The LIFESTAT project combines invasive human experiments, biomedical analyses, nationwide surveys, epidemiological studies, qualitative interviews, media content analyses, and ethnographic participant observations. The study investigates the biological consequences of statin treatment; determines the mechanism(s) by which statin use causes muscle and mitochondrial dysfunction; and analyzes achievement of treatment goals, people's perception of disease risk, media influence on people's risk and health perception, and the way people manage to live with the risk (personally, socially and technologically). CONCLUSIONS THE ORIGINALITY AND SUCCESS OF LIFESTAT DEPEND ON AND DERIVE FROM ITS INTERDISCIPLINARY APPROACH, IN WHICH THE DISCIPLINES CONVERGE INTO THOROUGH AND HOLISTIC STUDY AND DESCRIBE THE IMPACT OF STATIN USE ON THE EVERYDAY LIFE OF STATIN USERS THIS HAS THE POTENTIAL FOR MUCH GREATER BENEFIT THAN ANY ONE OF THE DISCIPLINES ALONE INTEGRATING TRADITIONAL DISCIPLINES PROVIDES NOVEL PERSPECTIVES ON POTENTIAL CURRENT AND FUTURE SOCIAL, MEDICAL AND PERSONAL BENEFITS OF STATIN USE.