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Protective effect of probiotics in patients with non-alcoholic fatty liver disease.
Cai, GS, Su, H, Zhang, J
Medicine. 2020;99(32):e21464
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Non-alcoholic fatty liver disease (NAFLD) is common in people with obesity and is characterised by high amounts of fat stored in the liver. Diet and exercise are the standard treatments, however recent studies have indicated that the gut microbiota may have an important role. This randomised control trial of 140 patients with NAFLD, aimed to assess the effect of probiotics when added to standard therapy for 3 months. The results showed that although gut microbiota, some aspects of liver function, blood lipids and blood sugars were all improved in individuals on standard therapy, there were additional improvements in those on standard therapy plus probiotics. It was concluded that although standard therapy alone is adequate to improve NAFLD, probiotics plus standard therapy was superior to standard therapy alone and effective in treatment of NAFLD. This study could be used by health professionals to justify the addition of probiotics to standard therapy to further improve NAFLD outcomes.
Abstract
To investigate the effects of probiotics on liver function, glucose and lipids metabolism, and hepatic fatty deposition in patients with non-alcoholic fatty liver disease (NAFLD).Totally 140 NAFLD cases diagnosed in our hospital from March 2017 to March 2019 were randomly divided into the observation group and control group, 70 cases in each. The control group received the diet and exercise therapy, while the observation group received oral probiotics based on the control group, and the intervention in 2 groups lasted for 3 months. The indexes of liver function, glucose and lipids metabolism, NAFLD activity score (NAS), and conditions of fecal flora in 2 groups were compared before and after the treatment.Before the treatment, there were no significant differences on alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamine transferase (GGT), total bilirubin (TBIL), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), insulin resistance index (HOMA-IR), NAFLD activity score (NAS), and conditions of fecal flora in 2 groups (P > .05). After the treatment, ALT, AST, GGT, TC, TG, HOMA-IR, NAS, and conditions of fecal flora in the observation group were better than those in the control group, and the observation group was better after treatment than before. All these above differences were statistically significant (P < .05).Probiotics can improve some liver functions, glucose and lipids metabolism, hepatic fatty deposition in patients with NAFLD, which will enhance the therapeutic effects of NAFLD.
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Time-restricted feeding alters lipid and amino acid metabolite rhythmicity without perturbing clock gene expression.
Lundell, LS, Parr, EB, Devlin, BL, Ingerslev, LR, Altıntaş, A, Sato, S, Sassone-Corsi, P, Barrès, R, Zierath, JR, Hawley, JA
Nature communications. 2020;11(1):4643
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There is growing evidence that less time spent in the fasted state may lead to chronic metabolic disorders such as diabetes and cardio vascular disease. Time-restricted feeding (TRF) is a practical way to control dietary intake by extending the time spent fasting and improves markers of metabolic health in both animals and humans. The inbuilt day/night cycle (circadian rhythm) is another important factor in metabolic health. 11 men with overweight/obesity took part in this randomised cross-over trial. In order to understand the mechanisms behind the beneficial effects of short-term TRF, a range of metabolites from skeletal muscle and blood serum were measured after 5 days of TRF (8 h per day) and then 5 days of extended feeding (EXF, 15 h per day). In this study, TRF changed the daily rhythm of lipid and amino acid metabolism, without modulating the core circadian rhythm in skeletal muscle. Long-term studies of TRF versus EXF in humans in real life settings, using more advanced molecular techniques are required to determine the exact mechanisms underlying the health-related benefits of TRF.
Abstract
Time-restricted feeding (TRF) improves metabolism independent of dietary macronutrient composition or energy restriction. To elucidate mechanisms underpinning the effects of short-term TRF, we investigated skeletal muscle and serum metabolic and transcriptomic profiles from 11 men with overweight/obesity after TRF (8 h day-1) and extended feeding (EXF, 15 h day-1) in a randomised cross-over design (trial registration: ACTRN12617000165381). Here we show that muscle core clock gene expression was similar after both interventions. TRF increases the amplitude of oscillating muscle transcripts, but not muscle or serum metabolites. In muscle, TRF induces rhythmicity of several amino acid transporter genes and metabolites. In serum, lipids are the largest class of periodic metabolites, while the majority of phase-shifted metabolites are amino acid related. In conclusion, short-term TRF in overweight men affects the rhythmicity of serum and muscle metabolites and regulates the rhythmicity of genes controlling amino acid transport, without perturbing core clock gene expression.
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Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.
Demark-Wahnefried, W, Rogers, LQ, Gibson, JT, Harada, S, Frugé, AD, Oster, RA, Grizzle, WE, Norian, LA, Yang, ES, Della Manna, D, et al
International journal of cancer. 2020;146(10):2784-2796
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Obesity directly impacts survival in individuals with breast cancer. Previous studies in animals and at the cellular level have shown that calorie restriction and increased physical activity to achieve a negative energy balance may inhibit cancer progression, however effects in patients are unknown. This randomised control trial aimed to determine the impact of a pre surgery weight loss programme in 32 women with breast cancer on tumour biology and other markers of disease. The results were mixed and showed that proteins which bind to hormones involved in breast cancer were increased, which could decrease severity of disease. However, tumour biology was negatively affected; specific genes involved in breast cancer progression were increased and those involved in tumour suppression were decreased. Although this did result in no net effect on the rate at which new tumours were formed. It was concluded that although the study showed mixed results, ultimately the rate at which new tumours were formed remained unaffected. This trial could be used by healthcare professionals to understand that the role of negative energy intake in breast cancer development is complicated and warrants further research.
Abstract
Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1β, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.
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Lipid Metabolism Links Nutrient-Exercise Timing to Insulin Sensitivity in Men Classified as Overweight or Obese.
Edinburgh, RM, Bradley, HE, Abdullah, NF, Robinson, SL, Chrzanowski-Smith, OJ, Walhin, JP, Joanisse, S, Manolopoulos, KN, Philp, A, Hengist, A, et al
The Journal of clinical endocrinology and metabolism. 2020;105(3)
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Following exercise, various metabolic changes occur which may be of benefit in fighting diseases such as type 2 diabetes and obesity. However, the degree of change may vary depending on whether the exercise has been performed pre or post meal consumption. This 6-week randomised crossover trial of 30 overweight or obese men aimed to determine the effect of exercising before or after breakfast on the use of fats and sugars by the body. The results showed that exercise before breakfast increased fat and sugar use in the body and also resulted in the alteration of eight genes associated with metabolism. Exercise before carbohydrate consumption also increased lipid use and improved insulin sensitivity, however body composition was similar regardless of when exercise was performed. It was concluded that exercising in the fasted state can optimise the body’s response without having to change intensity or effort. This study could be used by health care professionals to advise patients with obesity or overweight that exercising whilst in the fasted state could optimise their outcomes without having to increase exercise intensity or frequency.
Abstract
CONTEXT Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. OBJECTIVE To assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism. DESIGN (1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study). SETTING General community. PARTICIPANTS Men with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study). INTERVENTIONS Moderate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion. RESULTS Acute Study-exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: -3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P < 0.01) and type II fibers (-1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P < 0.05). Training Study-postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P > 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs -21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P < 0.05). CONCLUSIONS Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.
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Effects of Roux-en-Y Gastric Bypass on Osteoclast Activity and Bone Density in Morbidly Obese Patients with Type 2 Diabetes.
Tangalakis, LL, Tabone, L, Spagnoli, A, Muehlbauer, M, Omotosho, P, Torquati, A
Obesity surgery. 2020;30(1):290-295
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Gastric surgery and the resultant weight loss can improve an individual’s outcomes in a number of diseases, such as heart disease and type 2 diabetes, however an unfortunate side effect is bone loss. Roux-en-Y gastric bypass is a process whereby the size of your stomach is significantly reduced, and it is unclear as to the effect this type of surgery has on bone density. This cohort study of sixty-one individuals who underwent Roux-en-Y gastric bypass aimed to determine the effect on bone density one year post surgery. The results showed that following surgery, bone resorption was increased compared to control and although bone density was similar between the two groups, bone mineral content and bone surface area were decreased. Women who were post-menopausal demonstrated diminished bone health, although this was not significant. It was concluded that Roux-en-Y gastric bypass surgery results in a negative impact on bone health. This study could be used by healthcare professionals to understand the importance of considering bone health when recommending surgery, especially in those at high-risk of bone loss such as post-menopausal women.
Abstract
INTRODUCTION Roux-en-Y gastric bypass (RYGB) is a well-established treatment for morbid obesity and type 2 diabetes. The effects of RYGB on bone metabolism and bone health are largely unknown. OBJECTIVE Determine the changes in osteoclast function and bone density 1 year after RYGB as compared with a control group undergoing a diabetes support and education program (DSE). DESIGN A prospective cohort study with patients matched for weight and age assigned to RYGB or DSE. SETTING Large academic institution. PATIENTS OR OTHER PARTICIPANTS Patients with type 2 diabetes mellitus and morbid obesity (body mass index greater than 35 kg/m2). INTERVENTION Subjects either received laparoscopic RYBG or DSE, which consisted of nutritional, exercise, and dietary counseling performed by a certified diabetic educator and a nutritionist three times over a year. MAIN OUTCOME MEASURE Osteoclast activity, bone mineral density. RESULTS One year after, intervention subjects undergoing RYGB have a 280% increase in osteoclast activity as compared with a 7.6% increase in the DSE control group (P < 0.001). Furthermore, there was a statistically significant increase in sclerostin levels in subjects undergoing RYGB compared with an increase in the control group. The total bone mineral density was statistically unchanged within 1 year of intervention in both groups. A statistically significant decrease in bone mineral density in the left ribs (decrease of 6.8%, P < 0.05) and lumbar spine (decrease of 4.0%, P < 0.05) was seen 1 year after RYGB. CONCLUSIONS There is a significant increase in osteoclast activity observed 1 year after RYGB; the long-term clinical implications of this increased bone metabolism are unknown.
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Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans.
Remie, CME, Roumans, KHM, Moonen, MPB, Connell, NJ, Havekes, B, Mevenkamp, J, Lindeboom, L, de Wit, VHW, van de Weijer, T, Aarts, SABM, et al
The American journal of clinical nutrition. 2020;112(2):413-426
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Nicotinamide riboside (NR) is a member of the vitamin B3 family, which is naturally found in the diet and may improve metabolic functions. Improved metabolism can improve several diseases such as type 2 diabetes and obesity. This 6-week randomised control trial of 13 overweight and obese men and women aimed to investigate the effect of NR supplementation on metabolism. The results showed that supplementation improved muscle metabolism and body fat percentage, although total body weight remained unchanged. Supplementation did not improve markers for pre-diabetes or heart function. It was concluded that NR supplementation may improve muscle metabolism, however no other health effects were observed. This study could be used by healthcare professionals to understand that supplementation with NR may improve muscle function in overweight and obese individuals.
Abstract
BACKGROUND Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. OBJECTIVES We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. METHODS A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. RESULTS Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. CONCLUSIONS NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664.
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Metabolic impact of weight loss induced reduction of adipose ACE-2 - Potential implication in COVID-19 infections?
Li, L, Spranger, L, Soll, D, Beer, F, Brachs, M, Spranger, J, Mai, K
Metabolism: clinical and experimental. 2020;113:154401
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Obesity is now recognised as a risk factor for increased severity of Covid-19 infections. ACE-2 is a protein that has many functions but also allows Covid-19 into cells and is particularly evident in body tissues, which store fat. It is therefore possible that Covid-19 will target fat-storing tissues in the body. This 12-month randomised control weight-loss intervention study of 143 obese individuals aimed to determine ACE-2 expression and whether it could be modified by weight loss. The results showed that ACE-2 was only present in fat storing tissue and not muscle tissue. Interestingly individuals with pre-diabetes or diabetes had the lowest levels of ACE-2. Weight loss resulted in reduced ACE-2 in fat storing tissue, which resulted in an improvement in markers for diabetes. It was concluded that reduction of ACE-2 in fat storing tissues as a result of weight loss can improve markers for diabetes and could impact the severity of Covid-19 infection. Healthcare professionals could use this study to understand how weight loss in patients with obesity could decrease their risk of severe Covid-19 infection.
Abstract
BACKGROUND & AIMS Angiotensin converting enzyme (ACE)-2 is a modulator of adipose tissue metabolism. However, human data of adipose ACE-2 is rarely available. Considering that, ACE-2 is believed to be the receptor responsible for cell entry of SARS-CoV-2, a better understanding of its regulation is desirable. We therefore characterized the modulation of subcutaneous adipose ACE-2 mRNA expression during weight loss and the impact of ACE-2 expression on weight loss induced short- and long-term improvements of glucose metabolism. METHODS 143 subjects (age > 18; BMI ≥ 27 kg/m2) were analyzed before and after a standardized 12-week dietary weight reduction program. Afterwards subjects were randomized to a 12-month lifestyle intervention or a control group (Maintain-Adults trial). Insulin sensitivity (IS) was estimated by HOMA-IR (as an estimate of liver IS) and ISIClamp (as an estimate of skeletal muscle IS). ACE-2 mRNA expression (ACE-2AT) was measured in subcutaneous adipose tissue before and after weight loss. RESULTS ACE-2AT was not affected by obesity, but was reduced in insulin resistant subjects. Weight loss resulted in a decline of ACE-2AT (29.0 (20.0-47.9) vs. 21.0 (13.0-31.0); p = 1.6 ∗ 10-7). A smaller reduction of ACE-2 AT (ΔACE-2AT) was associated with a larger improvement of ISIClamp (p = 0.013) during weight reduction over 3 months, but not with the extend of weight loss. The degree of changes in insulin resistance were preserved until month 12 and was also predicted by the weight loss induced degree of ΔACE-2AT (p = 0.011). CONCLUSIONS Our data indicate that subcutaneous adipose ACE-2 expression correlates with insulin sensitivity. Weight loss induced decline of subcutaneous adipose ACE-2 expression might affect short- and long-term improvement of myocellular insulin sensitivity, which might be also relevant in the context of ACE-2 downregulation by SARS-CoV-2. TRIAL REGISTRATION ClinicalTrials.gov number: NCT00850629, https://clinicaltrials.gov/ct2/show/NCT00850629, date of registration: February 25, 2009.
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Effect of inorganic nitrate on exercise capacity, mitochondria respiration, and vascular function in heart failure with reduced ejection fraction.
Woessner, MN, Neil, C, Saner, NJ, Goodman, CA, McIlvenna, LC, Ortiz de Zevallos, J, Garnham, A, Levinger, I, Allen, JD
Journal of applied physiology (Bethesda, Md. : 1985). 2020;128(5):1355-1364
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Patients with chronic heart failure (CHF) are characterised by reduced aerobic capacity (V ̇O2peak) and early fatigue. Improving V ̇O2peak is an important clinical goal in CHF as it is correlated with reduced mortality rate and increased quality of life. The main aim of this study was to test the hypothesis that chronic oral inorganic nitrate supplementation will improve V ̇O2peak during treadmill exercise in patients with heart failure with reduced ejection fraction (HFrEF). This study is a randomised, placebo-controlled, double-blind, crossover study. Nineteen participants were recruited, and 16 individuals with diagnosed HFrEF completed the study. Participants were randomised to consume either nitrate-rich beetroot juice (210 mL, 16 mmol nitrate) or a nitrate-depleted placebo for 5 days. Results show that in patients with HFrEF, chronic oral inorganic nitrate supplementation had no significant effect on aerobic exercise capacity, vascular function, peripheral and central blood pressures, or muscle respiration. Authors conclude that future studies should characterise the diversity and abundance of the oral microbiome in HFrEF to elucidate approaches that could lead to a potential benefit of oral nitrate supplementation.
Abstract
Chronic underperfusion of the skeletal muscle tissues is a contributor to a decrease in exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). This underperfusion is due, at least in part, to impaired nitric oxide (NO) bioavailability. Oral inorganic nitrate supplementation increases NO bioavailability and may be used to improve exercise capacity, vascular function, and mitochondrial respiration. Sixteen patients with HFrEF (fifteen men, 63 ± 4 yr, body mass index: 31.8 ± 2.1 kg/m2) participated in a randomized, double-blind, crossover design study. Following consumption of either nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo for 5 days, participants completed separate visits for assessment of exercise capacity, endothelial function, and muscle mitochondrial respiration. Participants then had a 2-wk washout before completion of the same protocol with the other intervention. Statistical significance was set a priori at P < 0.05, and between-treatment differences were analyzed via paired t test analysis. Following nitrate supplementation, both plasma nitrate and nitrite increased (933%, P < 0.001 and 94%, P < 0.05, respectively). No differences were observed for peak oxygen consumption (nitrate: 18.5 ± 1.4 mL·kg-1·min-1, placebo: 19.3 ± 1.4 mL·kg-1·min-1; P = 0.13) or time to exhaustion (nitrate: 1,165 ± 92 s, placebo: 1,207 ± 96 s; P = 0.16) following supplementation. There were no differences between interventions for measures of vascular function, mitochondrial respiratory function, or protein expression (all P > 0.05). Inorganic nitrate supplementation did not improve exercise capacity and skeletal muscle mitochondrial respiratory function in HFrEF. Future studies should explore alternative interventions to improve peripheral muscle tissue function in HFrEF.NEW & NOTEWORTHY This is the largest study to date to examine the effects of inorganic nitrate supplementation in patients with heart failure with reduced ejection fraction (HFrEF) and the first to include measures of vascular function and mitochondrial respiration. Although daily supplementation increased plasma nitrite, our data indicate that supplementation with inorganic nitrate as a standalone treatment is ineffective at improving exercise capacity, vascular function, or mitochondrial respiration in patients with HFrEF.
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Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men.
Dollerup, OL, Chubanava, S, Agerholm, M, Søndergård, SD, Altıntaş, A, Møller, AB, Høyer, KF, Ringgaard, S, Stødkilde-Jørgensen, H, Lavery, GG, et al
The Journal of physiology. 2020;598(4):731-754
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Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) boosts NAD+ levels. Boosting NAD+ metabolism has emerged as a promising strategy to counter age-related functional decline and promote healthy ageing. Progressive deterioration of mitochondrial function and NAD+ metabolism are hallmarks of ageing of human tissue. The aim of this study was to determine if NR supplementation in humans impacts NAD+ metabolism and mitochondrial respiration in skeletal muscle. This study is a randomised, double-blinded, placebo-controlled clinical trial. Participants were randomised into two groups: NR (n=20) and placebo (n=20). Results show that 12 weeks of oral NR supplementation (2000 mg/day) decreased nicotinamide phosphoribosyltransferase protein levels [an enzyme] in muscle without affecting cellular NAD+ content. Despite changes in nicotinamide phosphoribosyltransferase, neither beneficial nor detrimental effects on mitochondrial respiration, content or dynamics were observed in skeletal muscle. Authors conclude that NR supplementation does not enhance aspects of mitochondrial function in human skeletal muscle of middle-aged, obese, insulin-resistant healthy males.
Abstract
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.
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The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage.
Williamson, J, Hughes, CM, Cobley, JN, Davison, GW
Redox biology. 2020;36:101673
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Mitochondria have an established role in the life cycle of a cell, contributing to cellular networks aligned to metabolism, biosynthetic pathways, and apoptotic cell death. Exercise increases the univalent reduction of ground state molecular dioxygen to superoxide in skeletal muscle. The aim of this study was to determine whether (1) a bout of high-intensity intermittent exercise (HIIE) damaged mitochondrial (mt)DNA; and (2) Mitoquinone (MitoQ) [orally available mitochondrial-targeted coenzyme Q10] could prevent mtDNA damage. This study is a double-blind, randomized, placebo-controlled design. Twenty-four (n = 24) healthy, recreationally active males volunteered to take part in the study. The participants were allocated to two groups: MitoQ (n = 12) and placebo (n = 12), and subsequently took part in a two-phased supplementation trial. Results showed that: - exercise increased DNA damage in nucleus and mitochondria. In fact, HIIE damages mtDNA both systemically in lymphocytes and locally in muscle tissue, occurring in parallel with nuclear DNA damage. - chronic MitoQ supplementation offers a prophylactic effect. - MitoQ decreases exercise-induced DNA damage. Authors conclude that the notion that a protective effect of a mitochondria-targeted antioxidant is only unmasked by exercise, reinforces the value of interrogating multiple physiological states when appraising the efficacy of an antioxidant.
Abstract
High-intensity exercise damages mitochondrial DNA (mtDNA) in skeletal muscle. Whether MitoQ - a redox active mitochondrial targeted quinone - can reduce exercise-induced mtDNA damage is unknown. In a double-blind, randomized, placebo-controlled design, twenty-four healthy male participants consisting of two groups (placebo; n = 12, MitoQ; n = 12) performed an exercise trial of 4 x 4-min bouts at 90-95% of heart rate max. Participants completed an acute (20 mg MitoQ or placebo 1-h pre-exercise) and chronic (21 days of supplementation) phase. Blood and skeletal muscle were sampled immediately pre- and post-exercise and analysed for nuclear and mtDNA damage, lipid hydroperoxides, lipid soluble antioxidants, and the ascorbyl free radical. Exercise significantly increased nuclear and mtDNA damage across lymphocytes and muscle (P < 0.05), which was accompanied with changes in lipid hydroperoxides, ascorbyl free radical, and α-tocopherol (P < 0.05). Acute MitoQ treatment failed to impact any biomarker likely due to insufficient initial bioavailability. However, chronic MitoQ treatment attenuated nuclear (P < 0.05) and mtDNA damage in lymphocytes and muscle tissue (P < 0.05). Our work is the first to show a protective effect of chronic MitoQ supplementation on the mitochondrial and nuclear genomes in lymphocytes and human muscle tissue following exercise, which is important for genome stability.