Vitamin D and Endothelial Function Kim, Do-Houn; Meza, Cesar A; Clarke, Holly ...
Nutrients,
02/2020, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Vitamin D is known to elicit a vasoprotective effect, while vitamin D deficiency is a risk factor for endothelial dysfunction (ED). ED is characterized by reduced bioavailability of a potent ...endothelium-dependent vasodilator, nitric oxide (NO), and is an early event in the development of atherosclerosis. In endothelial cells, vitamin D regulates NO synthesis by mediating the activity of the endothelial NO synthase (eNOS). Under pathogenic conditions, the oxidative stress caused by excessive production of reactive oxygen species (ROS) facilitates NO degradation and suppresses NO synthesis, consequently reducing NO bioavailability. Vitamin D, however, counteracts the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces ROS, and improves antioxidant capacity by enhancing the activity of antioxidative enzymes such as superoxide dismutase. In addition to ROS, proinflammatory mediators such as TNF-α and IL-6 are risk factors for ED, restraining NO and eNOS bioactivity and upregulating the expression of various atherosclerotic factors through the NF-κB pathway. These proinflammatory activities are inhibited by vitamin D by suppressing NF-κB signaling and production of proinflammatory cytokines. In this review, we discuss the diverse activities of vitamin D in regulating NO bioavailability and endothelial function.
NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen ...species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.
Creatine is a naturally occurring compound, functioning in conjunction with creatine kinase to play a quintessential role in both cellular energy provision and intracellular energy shuttling. An ...extensive body of literature solidifies the plethora of ergogenic benefits gained following dietary creatine supplementation; however, recent findings have further indicated a potential therapeutic role for creatine in several pathologies such as myopathies, neurodegenerative disorders, metabolic disturbances, chronic kidney disease and inflammatory diseases. Furthermore, creatine has been found to exhibit non-energy-related properties, such as serving as a potential antioxidant and anti-inflammatory. Despite the therapeutic success of creatine supplementation in varying clinical populations, there is scarce information regarding the potential application of creatine for combatting the current leading cause of mortality, cardiovascular disease (CVD). Taking into consideration the broad ergogenic and non-energy-related actions of creatine, we hypothesize that creatine supplementation may be a potential therapeutic strategy for improving vascular health in at-risk populations such as older adults or those with CVD. With an extensive literature search, we have found only four clinical studies that have investigated the direct effect of creatine on vascular health and function. In this review, we aim to give a short background on the pleiotropic applications of creatine, and to then summarize the current literature surrounding creatine and vascular health. Furthermore, we discuss the varying mechanisms by which creatine could benefit vascular health and function, such as the impact of creatine supplementation upon inflammation and oxidative stress.
Abstract Purpose The appropriate mode of exercise training for cancer cachexia is not well-established. Using the colon-26 (C26) mouse model of cancer cachexia, we defined and compared the skeletal ...muscle responses to aerobic and resistance training. Methods Twelve-month old Balb/c mice were initially assigned to Control, Aerobic Training (AT; wheel running), or Resistance Training (RT; ladder climbing) (n = 16-17/group). After 8 weeks of training, half of each group was injected with C26 tumor cells, followed by 3 additional weeks of training. Body composition and neuromuscular function was evaluated pre- and post-training. Muscles were collected post-training and analyzed for fiber cross-sectional area (CSA), Akt-mTOR signaling, and expression of insulin-like growth factor-I (IGF-I) and myogenic regulatory factors. Results Total body mass decreased (p < 0.05) in C26 (-8%), AT + C26 (-18%), and RT + C26 (-15%) but not Control. Sensorimotor function declined (p < 0.05) in Control (-16%), C26 (-13%), and RT + C26 (-23%) but not AT + C26. Similarly, strength/body weight decreased (p < 0.05) in Control (-7%), C26 (-21%), and RT + C26 (-10%) but not AT + C26. Gastrocnemius mass/body weight tended to be greater in AT + C26 vs. C26 (+ 6%, p = 0.09). Enlargement of the spleen was partially corrected in AT + C26 (-27% vs. C26, p < 0.05). Fiber CSA was lower in all C26 groups vs. Control (-32-46%, p < 0.05); however, the effect size calculated from C26 and AT + C26 was large (+ 24%, d = 1.04). Phosphorylated levels of mTOR in AT + C26 exceeded C26 (+ 31%, p < 0.05). RT + C26 showed greater mRNA expression (p < 0.05) of IGF-IEa (+ 79%) and myogenin (+ 126%) with a strong tendency for greater IGF-IEb (+ 127%, p = 0.069) vs. Control. Conclusions Aerobic or resistance training was unable to prevent tumor-induced body weight loss. However, aerobic training may have preserved function, reduced the inflammatory response of the spleen, and marginally rescued muscle mass possibly through activation of mTOR. Aerobic training may therefore have therapeutic value for patients with cancer cachexia. In contrast, resistance training induced the expression of genes associated with muscle damage and repair. This gene response may be supportive of excessive stress generated by high resistance loading in a tumor-bearing state.
Vitamin D (VitD) possesses antiadipogenic and ergogenic properties that could be effective to counteract obesity-related adverse health consequences. Therefore, our overall hypothesis was that VitD ...could ameliorate obesity-induced insulin resistance, systemic inflammation, and loss of skeletal muscle mass and function in an obesity animal model, p62-deficient mice. Furthermore, it was hypothesized that resistance exercise training (RT) could enhance the benefits of VitD by upregulating protein expression of vitamin D receptor in skeletal muscle. Forty 24-week-old male p62-deficient mice were assigned to the following 4 groups (10/group) for a 10-week intervention: control (p62C, no treatment), VitD (VD, 1000 IU vitamin D3/kg/d), RT (ladder climbing, 3 times per week), or combined treatment (VRT, VD + RT). Serum VitD levels increased in VD and VRT (P < .05). Total body mass increased in p62C, VD, and VRT, but fat mass increased only in p62C (P < .05). Loss of skeletal muscle function was reported only in p62C (P < .05). Improved blood glucose levels and lower spleen mass were reported in RT and VRT compared to p62C (P < .05). However, the hindlimb muscle wet weights; myofiber cross-sectional area; and expression levels of the regulatory proteins for insulin signaling, inflammation, and muscle growth were not changed by any intervention. In conclusion, VitD administration attenuated the progression of obesity and preserved skeletal muscle function in p62-deficient mice. However, the obese mice improved systemic insulin sensitivity and inflammation only when the intervention involved RT.
This investigation evaluated the efficacy by which resistance training enhances body composition, metabolic, and functional outcomes for obese patients undergoing a 12-week medically supervised ...hypocaloric treatment.
This was a single-blind, randomized, parallel-group prospective trial. Morbidly obese patients were prescribed a 12-week proprietary very low calorie diet (VLCD) treatment (Optifast®) with supplemental protein (1120 kcals/day) and were placed in one of two groups for 14 weeks: 1) Standard Treatment Control (CON) (n = 5) or 2) Resistance Training (RT) (n = 6). Both groups underwent a pedometer-based walking program; however only RT performed resistance training 3 days/week for 12 weeks. Body composition, resting energy expenditure (REE), neuromuscular function, and serum biomarkers were measured at weeks 0, 6, and 13.
Both groups exhibited a significant loss of total body mass (TBM) (CON: −19.4 ± 2.3 kg, p = 0.0009 vs. RT: −15.8 ± 1.5 kg, p = 0.0002) and fat mass (FM) (CON: −14.7 ± 1.8 kg, p = 0.0002 vs. RT: −15.1 ± 2.1 kg, p = 0.0002) with no group differences. CON lost 4.6 ± 0.8 kg (p = 0.004) of lean mass (LM) while RT demonstrated no changes. Group differences were found for the relative proportion of total weight-loss due to FM-loss (CON: 75.6 ± 3.4% vs. RT: 96.0 ± 6.0%, p = 0.03) and LM-loss (CON: 24.4 ± 3.2% vs. RT: 4.0 ± 6.5%, p = 0.03). CON demonstrated a 328.6 ± 72.7 kcal/day (−14.3 ± 2.4%) (p = 0.02) decrease in REE while RT exhibited a non-significant decrease of 4.6 ± 1.6% (p = 0.78). RT demonstrated greater improvements in all measures of contractile function and strength when compared to CON (p < 0.05). At post-treatment, RT exhibited greater serum free fatty acids (p = 0.01), glycerol (p = 0.003), and β-hydroxybutyrate (p = 0.005) than CON.
Resistance training was advantageous for weight-loss composition by preservation of LM without compromising overall weight- or fat-loss in morbidly obese men and women undergoing a protein supplemented VLCD. These changes accompanied positive adaptations for resting metabolism and muscular function.
Introduction
Excessive reactive oxygen species (ROS) production is a prominent feature of obesity‐related conditions including impairments in endothelial function. NADPH oxidases (Nox) and ...mitochondria are major sources of ROS production within the vasculature. However, studies involving direct measurement of in vivo ROS production are limited in humans. Thus, the relative contributions of Nox‐ and mitochondrial‐derived ROS in human obesity remain to be fully characterized.
The objective of this study was to determine the predominant sources of in vivo ROS production in the skeletal muscle microvasculature of individuals with obesity. We hypothesize that both Nox‐ and mitochondria‐dependent ROS production are upregulated in human obesity.
Methods
Two sedentary men with Class II and above obesity (body mass index ≥ 35 kg/m2) and the Metabolic Syndrome were studied. Microdialysis was used for measurements of in vivo skeletal muscle ROS production. Microdialysis probes were perfused with saline containing Amplex Ultrared, horseradish peroxidase and superoxide dismutase to measure local hydrogen peroxide and superoxide concentrations. To assess ROS production from distinct sources, microdialysis probes were perfused with the following: apocynin (non‐specific Nox inhibitor), MitoTEMPO (mitochondrial‐ROS inhibitor), and GKT 137831 (specific Nox 4 inhibitor).
Results
The concentrations of hydrogen peroxide and superoxide decreased upon addition of apocynin to microdialysis probes (mean ± SEM; hydrogen peroxide: 1.18 ± 0.58 to 0.76 ± 0.01 μM; superoxide: 1.47 ± 0.46 to 1.10 ± 0.62 μM). MitoTEMPO perfusion elicited an increase in hydrogen peroxide (1.12 ± 0.76 to 1.51 ± 1.08 μM) and decrease in superoxide (1.47 ± 0.46 to 0.78 ± 0.10 μM). The combination of apocynin plus MitoTEMPO resulted in concentrations of hydrogen peroxide (0.22 ± 0.10 μM) and superoxide (0.23 ± 0.06 μM) that were 69.7% and 79.1% lower than apocynin alone. In addition, the hydrogen peroxide (0.56 ± 0.25 μM) and superoxide (0.43 ± 0.18 μM) concentrations with co‐perfusion of apocynin and GKT were 26.3% and 60.9% lower than with apocynin alone.
Conclusions
Our preliminary data suggest that mitochondria and Nox together are significant sources of ROS production within the skeletal muscle microvasculature of obese individuals. The local inhibition of Nox‐ and mitochondrial‐derived ROS resulted in marked decreases in extracellular ROS levels within the skeletal muscle microvasculature. Although the small sample size currently limits our interpretation of the results, this study is anticipated to become the first to report on distinct sources of in vivo ROS production in human obesity.
Abstract only
The cold pressor test (CPT) has been widely used to assess both cardiovascular and hemodynamic responses to stress. Despite the broad utilization of the CPT, there have been few if any ...studies in which metabolomic profiling was used to study the metabolic response to such a stimulus. Metabolomics allows insight into varying chemical processes, displaying detailed profiles of metabolites, small molecule substrates, intermediates and products of metabolism. The purpose of this study was to investigate the influence of sympathetic activation induced by a 1‐minute cold‐water immersion CPT, upon muscle metabolic responses, through metabolomics profiling of muscle interstitial fluid in adults. Five healthy adults (2 males, 3 females; 29.4 ± 9.4 yrs.; 77.6 ± 19.3 kg) were recruited for this pilot study. Three microdialysis probes (CMA 20, CMA/Microdialysis, Stockholm, Sweden) were percutaneously inserted into the vastus lateralis muscle of the dominant leg using sterile technique. Probes were then perfused with sterile saline containing 5 mM ethanol through the inlet tubing at a rate of 2.0 μL/min, and dialysate from the outlet tubing was collected in 150 μL polyethylene collection vials. One hour (3 × 20‐minute collections) of basal dialysates were collected and pooled. Participants then completed, in a seated position, a CPT in which the right hand was immersed up to the wrist in ice water for 1 minute. A 20‐min dialysate sample was collected during and immediately following the CPT. Microdialysis samples were sent to the West Coast Metabolomics Center (UC Davis Genome Center, Davis, CA, USA) for metabolomic profiling. Enzymatic‐fluorometric ethanol assay was also used to measure ethanol outflow: inflow (O:I) ratio to determine microvascular blood flow. The percent change from pre‐CPT to the CPT sample was calculated for every metabolite found. Data were then sorted on a magnitude basis, from smallest to largest change from basal levels. From the 413 metabolites detected, 207 were found to increase and 206 were found to decrease from baseline to post‐CPT. Nine metabolites were found within the 95
th
to 100
th
percentile of positive change from baseline to CPT, including: 1‐monostearin (median: 50.4%; range: 10.0–183.1), 3‐aminoisobutyric acid (median: 52.5%; range: 39.2–95.4), palmitoleic acid (median: 92.2%; range: 35.4–204.5); and 6 “unknown metabolites.” Furthermore, 5 “unknown metabolites” were also detected within the 95
th
to 100
th
percentile of negative change (decrease from baseline). Ethanol O:I ratio increased baseline to CPT, indicating decreased blood flow (0.483 ± 0.088 to 0.547 ± 0.027, mean ±
SEM
). These results indicate that the CPT can elicit both vasoconstriction and a notable metabolic response in muscle tissue, identifiable by the use of ethanol analysis and metabolomics of dialysate from microdialysis of skeletal muscle. Of specific interest, 1‐monostearin and palmitoleic acid were found to be in the group of molecules that increased the most in response to CPT. Although speculative, increased adrenergic stimulation resulting from CPT‐induced sympathetic activation may have resulted in liberation of 1‐monostearin and palmitoleic acid from membranes or other locations, or from increases in desaturase activities.
Introduction
Type 2 diabetes (T2D) in elderly patients is associated with accelerated loss of skeletal muscle mass and strength. However, there are few meta-analysis reviews which investigate the ...effects of resistance training (RT) on glycemic control and skeletal muscle in the patients.
Methods
Three electronic databases were searched (from the earliest date available to November 2016). Studies were included according to the inclusion criteria: T2D patients at least 60 years old, fasting plasma glucose of at least 7.0, and at least 8 weeks of RT.
Results
Fifteen cohorts of eight studies (360 patients, average age 66 years) met the inclusion criteria. RT groups lowered glycosylated hemoglobin (HbA1c) (mean ES = −0.37, 95% CI = −0.55 to −0.20,
P
< 0.01) but did not result in a significant effect on lean body mass (LBM) (mean ES = 0.08, 95% CI = −0.15 to 0.30,
P
= 0.50). Homogeneity was shown between studies regarding HbA1c and LBM (
Q
= 15.70,
df
= 9,
P
= 0.07 and
Q
= 0.12,
df
= 4,
P
= 0.998, respectively). High-intensity subgroups showed a slight tendency to improve (rather than duration, frequency, and weekly volume) and to decrease HbA1c levels more than low-intensity subgroups (
P
= 0.37). RT increased muscular strength (mean ES = 1.05, 95% CI = 0.26–1.84,
P
= 0.01). No training components explained the heterogeneity between studies with changes in muscle strength.
Conclusion
RT improves glycemic control and muscle strength in elderly patients with T2D. RT with high intensity can be a strategy to treat patients with T2D and sarcopenia associated with aging.
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