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Context:Low-grade inflammation is associated with obesity and the metabolic syndrome (MetS). Preclinical evidence suggests that resveratrol (RSV) has beneficial metabolic and anti-inflammatory effects that could have therapeutic implications.Objective:To investigate effects of long-term RSV treatment on inflammation and MetS.Setting and Design:A randomized, placebo-controlled, double-blind, parallel group clinical trial conducted at Aarhus University Hospital.Participants:Middle-aged community-dwelling men (N = 74) with MetS, 66 of whom completed all visits (mean ± standard error of the mean): age, 49.5 ± 0.796 years; body mass index, 33.8 ± 0.44 kg/m2; waist circumference, 115 ± 1.14 cm.Intervention:Daily oral supplementation with 1000 mg RSV (RSVhigh), 150 mg RSV, or placebo for 16 weeks.Main outcome measures:Plasma levels of high-sensitivity C-reactive protein (hs-CRP), circulating lipids, and inflammatory markers in circulation and adipose/muscle tissue biopsy specimens; glucose metabolism; and body composition including visceral fat and ectopic fat deposition.Results:RSV treatment did not lower circulating levels of hs-CRP, interleukin 6, or soluble urokinase plasminogen activator receptor in plasma, and inflammatory gene expression in adipose and muscle tissues also remained unchanged. RSV treatment had no effect on blood pressure, body composition, and lipid deposition in the liver or striated muscle. RSV treatment had no beneficial effect on glucose or lipid metabolism. RSVhigh treatment significantly increased total cholesterol (P < 0.002), low-density lipoprotein (LDL) cholesterol (P < 0.006), and fructosamine (P < 0.013) levels compared with placebo.Conclusion:RSV treatment did not improve inflammatory status, glucose homeostasis, blood pressure, or hepatic lipid content in middle-aged men with MetS. On the contrary, RSVhigh significantly increased total cholesterol, LDL cholesterol, and fructosamine levels compared with placebo.Neither high- nor low-dose resveratrol had beneficial effects on inflammation or the metabolic syndrome in middle-aged men. High-dose treatment increased lipid and fructosamine levels.

Excess body weight and insulin resistance lead to type 2 diabetes and other major health problems. There is an urgent need for dietary interventions to address these conditions. To measure the effects of a low-fat vegan diet on body weight, insulin resistance, postprandial metabolism, and intramyocellular and hepatocellular lipid levels in overweight adults. This 16-week randomized clinical trial was conducted between January 2017 and February 2019 in Washington, DC. Of 3115 people who responded to flyers in medical offices and newspaper and radio advertisements, 244 met the participation criteria (age 25 to 75 years; body mass index of 28 to 40) after having been screened by telephone. Participants were randomized in a 1:1 ratio. The intervention group (n = 122) was asked to follow a low-fat vegan diet and the control group (n = 122) to make no diet changes for 16 weeks. At weeks 0 and 16, body weight was assessed using a calibrated scale. Body composition and visceral fat were measured by dual x-ray absorptiometry. Insulin resistance was assessed with the homeostasis model assessment index and the predicted insulin sensitivity index (PREDIM). Thermic effect of food was measured by indirect calorimetry over 3 hours after a standard liquid breakfast (720 kcal). In a subset of participants (n = 44), hepatocellular and intramyocellular lipids were quantified by proton magnetic resonance spectroscopy. Repeated measure analysis of variance was used for statistical analysis. Among the 244 participants in the study, 211 (87%) were female, 117 (48%) were White, and the mean (SD) age was 54.4 (11.6) years. Over the 16 weeks, body weight decreased in the intervention group by 5.9 kg (95% CI, 5.0-6.7 kg; P < .001). Thermic effect of food increased in the intervention group by 14.1% (95% CI, 6.5-20.4; P < .001). The homeostasis model assessment index decreased (-1.3; 95% CI, -2.2 to -0.3; P < .001) and PREDIM increased (0.9; 95% CI, 0.5-1.2; P < .001) in the intervention group. Hepatocellular lipid levels decreased in the intervention group by 34.4%, from a mean (SD) of 3.2% (2.9%) to 2.4% (2.2%) (P = .002), and intramyocellular lipid levels decreased by 10.4%, from a mean (SD) of 1.6 (1.1) to 1.5 (1.0) (P = .03). None of these variables changed significantly in the control group over the 16 weeks. The change in PREDIM correlated negatively with the change in body weight (r = -0.43; P < .001). Changes in hepatocellular and intramyocellular lipid levels correlated with changes in insulin resistance (both r = 0.51; P = .01). A low-fat plant-based dietary intervention reduces body weight by reducing energy intake and increasing postprandial metabolism. The changes are associated with reductions in hepatocellular and intramyocellular fat and increased insulin sensitivity. ClinicalTrials.gov Identifier: NCT02939638.

Aging causes skeletal muscle atrophy, and myofiber loss can be a critical component of this process. In 1989, Rosenberg emphasized the importance of the loss of skeletal muscle mass that occurs with aging and coined the term 'sarcopenia'. Since then, sarcopenia has attracted considerable attention due to the aging population in developed countries. The presence of sarcopenia is closely related to staggering, falls and even frailty in the elderly, which in turn leads to the need for nursing care. Sarcopenia is often associated with a poor prognosis in the elderly. Therefore, it is crucial to investigate the causes and pathogenesis of sarcopenia, and to develop and introduce interventional strategies in line with these causes and pathogenesis. Sarcopenia can be a primary component of physical frailty. The association between sarcopenia, frailty and locomotive syndrome is complex; however, sarcopenia is a muscle-specific concept that is relatively easy to approach in research. In the elderly, a lack of exercise, malnutrition and hormonal changes lead to neuromuscular junction insufficiency, impaired capillary blood flow, reduced repair and regeneration capacity due to a decrease in the number of muscle satellite cells, the infiltration of inflammatory cells and oxidative stress, resulting in muscle protein degradation exceeding synthesis. In addition, mitochondrial dysfunction causes metabolic abnormalities, such as insulin resistance, which may lead to quantitative and qualitative abnormalities in skeletal muscle, resulting in sarcopenia. The present review article focuses on age-related primary sarcopenia and outlines its pathogenesis and mechanisms.

Abstract Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH). Methods We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry. Results Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass. Conclusions These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.

Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy. The muscle-secreted, exercise-induced peptide hormone apelin decreases with aging and sarcopenia, and its repletion in aged mice with recombinant protein improves muscle mass and function.

Skeletal muscle conveys several of the health-promoting effects of exercise; yet the underlying mechanisms are not fully elucidated. Studying skeletal muscle is challenging due to its different fiber types and the presence of non-muscle cells. This can be circumvented by isolation of single muscle fibers. Here, we develop a workflow enabling proteomics analysis of pools of isolated muscle fibers from freeze-dried human muscle biopsies. We identify more than 4000 proteins in slow- and fast-twitch muscle fibers. Exercise training alters expression of 237 and 172 proteins in slow- and fast-twitch muscle fibers, respectively. Interestingly, expression levels of secreted proteins and proteins involved in transcription, mitochondrial metabolism, Ca 2+ signaling, and fat and glucose metabolism adapts to training in a fiber type-specific manner. Our data provide a resource to elucidate molecular mechanisms underlying muscle function and health, and our workflow allows fiber type-specific proteomic analyses of snap-frozen non-embedded human muscle biopsies. Skeletal muscle conveys the beneficial effects of physical exercise but due to its heterogeneity, studying the effects of exercise on muscle fibres is challenging. Here, the authors carry out proteomic analysis of myofibres from freeze-dried muscle biopsies, show fibre-type specific changes in response to exercise, and show that the oxidative and glycolytic muscle fibers adapt differentially to exercise training.

Abstract Context Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR). Objective In a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle. Design Seventy-six women (body mass index, 25-40 kg/m2) were randomly assigned to 1 of 3 diets for 8 weeks and provided foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast prior to a 24-hour fast on 3 nonconsecutive days per week. On nonfasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, nonesterified fatty acids (NEFAs), β-hydroxybutyrate (BHB), and markers of lipid metabolism and oxidative stress in muscle by quantitative polymerase chain reaction were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups). Results IF70 resulted in greater weight and fat loss and reduced NEFAs vs CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes glutathione peroxidase 1 (GPX1), superoxide dismutase 1, soluble (SOD1), and SOD2 vs CR70. Fasting for 24 hours increased NEFAs and BHB in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels. Conclusions In comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.

Sustained nutrient (fuel) excess, as occurs during obesity and diabetes, has been linked to increased inflammation, impaired mitochondrial homeostasis, lipotoxicity, and insulin resistance in skeletal muscle. Precisely how mitochondrial dysfunction is initiated and whether it contributes to insulin resistance in this tissue remains a poorly resolved issue. Herein, we examine the contribution that an increase in proinflammatory NFkB signalling makes towards regulation of mitochondrial bioenergetics, morphology, and dynamics and its impact upon insulin action in skeletal muscle cells subject to chronic fuel (glucose and palmitate) overloading. We show sustained nutrient excess of L6 myotubes promotes activation of the IKKβ-NFkB pathway (as judged by a six-fold increase in IL-6 mRNA expression; an NFkB target gene) and that this was associated with a marked reduction in mitochondrial respiratory capacity (>50%), a three-fold increase in mitochondrial fragmentation and 2.5-fold increase in mitophagy. Under these circumstances, we also noted a reduction in the mRNA and protein abundance of PGC1α and that of key mitochondrial components (SDHA, ANT-1, UCP3, and MFN2) as well as an increase in cellular ROS and impaired insulin action in myotubes. Strikingly, pharmacological or genetic repression of NFkB activity ameliorated disturbances in mitochondrial respiratory function/morphology, attenuated loss of SDHA, ANT-1, UCP3, and MFN2 and mitigated the increase in ROS and the associated reduction in myotube insulin sensitivity. Our findings indicate that sustained oversupply of metabolic fuel to skeletal muscle cells induces heightened NFkB signalling and that this serves as a critical driver for disturbances in mitochondrial function and morphology, redox status, and insulin signalling.