1.
Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.
Axelrod, CL, Fealy, CE, Erickson, ML, Davuluri, G, Fujioka, H, Dantas, WS, Huang, E, Pergola, K, Mey, JT, King, WT, et al
Metabolism: clinical and experimental. 2021;121:154803
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Insulin resistance is a key pathophysiological mechanism in the development and progression of type 2 diabetes. Abnormalities in lipid metabolism and ectopic lipid accumulation are known to directly contribute to the onset of insulin resistance. Authors hypothesised that lipid infusion would increase dynamin related protein 1 [a type of protein]-mediated mitochondrial fission in skeletal muscle independent of function and content, consequently reducing peripheral insulin sensitivity. The study included sedentary but otherwise healthy adults who were prospectively randomized to receive either lipid or saline infusion to isolate the direct contribution of fatty acids to skeletal muscle mitochondrial dynamics. Results show that mitochondrial fission and quality control networks are activated in response to lipid infusion which occurs independent of changes in mitochondrial content or capacity and contributes to the onset of insulin resistance in healthy humans. Authors conclude that treatments that limit lipid-induced activation of mitochondrial fission and/or quality control processes may have therapeutic value in the treatment of insulin resistance.
Abstract
BACKGROUND AND AIMS A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION NCT02697201, ClinicalTrials.gov.
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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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Silymarin in the prevention and treatment of liver diseases and primary liver cancer.
Féher, J, Lengyel, G
Current pharmaceutical biotechnology. 2012;13(1):210-7
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Non-alcoholic fatty liver disease (NAFLD) is a recognised health problem with no convincing interventions to date. This randomised trial aimed to examine the efficacy of silymarin plus vitamin E in the treatment of NAFLD. 36 patients were randomized to either group Ι or group ΙΙ. Group Ι was treated with 2 tablets of silymarin plus vitamin E per day, hypocaloric diet and exercise. Group ΙΙ was treated only with a hypocaloric diet. Study duration was 3 months for both groups. Diagnosis of NAFLD was confirmed for all participants by liver biopsy. Patients in group Ι showed significant decrease in anthropometric measurements. Both groups experienced reductions in markers of NAFLD, however in group I, these reductions were independent of weight loss, whereas in group II, those who failed to lose 5% of body weight didn’t show a change in biochemical markers. Authors conclude that intervention with silymarin plus vitamin E, alone or along with other treatments, can help NAFLD patients who fail to lose weight with diet.
Abstract
In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and chemical-induced hepatic toxicity), the antioxidant medicines such as silymarin can have beneficial effect. Liver cirrhosis, non-alcoholic fatty liver and steatohepatitis are risk factors for hepatocellular carcinoma (HCC). Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients. The silymarin exerts membrane-stabilizing and antioxidant activity, it promotes hepatocyte regeneration; furthermore it reduces the inflammatory reaction, and inhibits the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies the long-term administration of silymarin significantly increased survival time of patients with alcohol induced liver cirrhosis. Based on the results of studies using methods of molecular biology, silymarin can significantly reduce tumor cell proliferation, angiogenesis as well as insulin resistance. Furthermore, it exerts an anti-atherosclerotic effect, and suppresses tumor necrosis factor-alpha-induced protein production and mRNA expression due to adhesion molecules. The chemopreventive effect of silymarin on HCC has been established in several studies using in vitro and in vivo methods; it can exert a beneficial effect on the balance of cell survival and apoptosis by interfering cytokines. In addition to this, anti-inflammatory activity and inhibitory effect of silymarin on the development of metastases have also been detected. In some neoplastic diseases silymarin can be administered as adjuvant therapy as well.