Human skeletal muscle nitrate and nitrite in individuals with peripheral arterial disease: Effect of inorganic nitrate supplementation and exercise.

Skeletal muscle may act as a reservoir for N-oxides following inorganic nitrate supplementation. This idea is most intriguing in individuals with peripheral artery disease (PAD) who are unable to endogenously upregulate nitric oxide. This study analyzed plasma and skeletal muscle nitrate and nitrite concentrations along with exercise performance, prior to and following 12-weeks of exercise training combined with oral inorganic nitrate supplementation (EX+BR) or placebo (EX+PL) in participants with PAD. Non-supplemented, at baseline, there were no differences in plasma and muscle nitrate. For nitrite, muscle concentration was higher than plasma (+0.10 nmol.g-1 ). After 12 -weeks, acute oral nitrate increased both plasma and muscle nitrate (455.04 and 121.14 nmol.g-1 , p < 0.01), which were correlated (r = 0.63, p < 0.01), plasma nitrate increase was greater than in muscle (p < 0.01). Nitrite increased in the plasma (1.01 nmol.g-1 , p < 0.05) but not in the muscle (0.22 nmol.g-1 ) (p < 0.05 between compartments). Peak walk time (PWT) increased in both groups (PL + 257.6 s;BR + 315.0 s). Six-minute walk (6 MW) distance increased only in the (EX+BR) group (BR + 75.4 m). We report no substantial gradient of nitrate (or nitrite) from skeletal muscle to plasma, suggesting a lack of reservoir-like function in participants with PAD. Oral nitrate supplementation produced increases in skeletal muscle nitrate, but not skeletal muscle nitrite. The related changes in nitrate concentration between plasma and muscle suggests a potential for inter-compartmental nitrate "communication". Skeletal muscle did not appear to play a role in within compartment nitrate reduction. Muscle nitrate and nitrite concentrations did not appear to contribute to exercise performance in patients with PAD.

Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitrogen handling were strongly associated with glycine in correlation analyses. Stable isotope labeling in Zucker fatty rats (ZFRs) shows that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner. Inhibition of the BCAA transaminase (BCAT) enzymes depletes plasma pools of alanine and raises glycine levels. In high-fat-fed ZFRs, dietary glycine supplementation raises urinary acyl-glycine content and lowers circulating triglycerides but also results in accumulation of long-chain acyl-coenzyme As (acyl-CoAs), lower 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in muscle, and no improvement in glucose tolerance. Collectively, these studies frame a mechanism for explaining obesity-related glycine depletion and also provide insight into the impact of glycine supplementation on systemic glucose, lipid, and amino acid metabolism.

Beet the Best?

RATIONALE: A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions. OBJECTIVE: To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication. METHODS AND RESULTS: This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2±57.3 s for the exercise plus placebo group (n=13) and by 180.3±46.6 s for the exercise plus beetroot juice group (n=11; P≤0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, -0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6±12.1 and 53.3±19.6 m ( P≤0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to-large effect sizes over exercise plus placebo changes. CONCLUSIONS: Although it is premature to speculate on overall clinical utility of a nitrate-based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite before exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session, thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01684930 and NCT01785524.

Effects of a 12-Week mHealth Program on FunctionalCapacity and Physical Activity in Patients With PeripheralArtery Disease.

Supervised exercise is beneficial for peripheral artery disease (PAD) patients limited by intermittent claudication (IC). However, supervised exercise for PAD remains widely underutilized. Mobile health (mHealth) provides an intermediate solution between supervised and independent home-based exercise. The purpose of this study was to determine the effects on functional capacity and physical activity patterns of a 12-week mHealth program in PAD patients with IC. Twenty patients were randomized into usual care or a 12-week mHealth intervention consisting of patient education, smartphones, and physical activity trackers. Patient education was disseminated through smartphone and a daily exercise prescription was given based on steps per day. Primary outcomes were 12-week changes in peak VO2 and claudication onset time; and changes in physical activity measured by steps per/day and minutes of exercise per/week. mHealth patients significantly increased peak VO2 from 15.2 ± 4.3 to 18.0 ± 4.8 ml/kg/min (20.3 ± 26.4%; p ≤0.05), while usual care did not change from 14.3 ± 5.4 to 14.5 ± 5.7 ml/kg/min (1.0 ± 6.9%; NS). Comparison of these changes resulted in a significant difference between groups (p ≤0.05) for peak VO2. Claudication onset time significantly increased in mHealth (320 ± 226 to 525 ± 252 seconds; ≤ 0.05), while usual care demonstrated a worsening (252 ± 256 to 231 ± 196 seconds; NS). The comparison of these group changes resulted in a significant difference (p ≤0.05). Neither steps per day or minutes of activity reached significant differences between groups. In conclusion, a 12-week mHealth program in PAD patients with IC can improve peak VO2 and claudication onset time; and mHealth interventions represent a promising alternative therapy for those patients who cannot participate in supervised exercise.

Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease.

Peripheral arterial disease (PAD) results in a failure to adequately supply blood and oxygen (O(2)) to working tissues and presents as claudication pain during walking. Nitric oxide (NO) bioavailability is essential for vascular health and function. Plasma nitrite (NO(2)(-)) is a marker of vascular NO production but may also be a protected circulating "source" that can be converted to NO during hypoxic conditions, possibly aiding perfusion. We hypothesized that dietary supplementation of inorganic nitrate in the form of beetroot (BR) juice would increase plasma NO(2)(-) concentration, increase exercise tolerance, and decrease gastrocnemius fractional O(2) extraction, compared with placebo (PL). This was a randomized, open-label, crossover study. At each visit, subjects (n = 8) underwent resting blood draws, followed by consumption of 500 ml BR or PL and subsequent blood draws prior to, during, and following a maximal cardiopulmonary exercise (CPX) test. Gastrocnemius oxygenation during the CPX was measured by near-infrared spectroscopy. There were no changes from rest for [NO(2)(-)] (152 ± 72 nM) following PL. BR increased plasma [NO(2)(-)] after 3 h (943 ± 826 nM; P ≤ 0.01). Subjects walked 18% longer before the onset of claudication pain (183 ± 84 s vs. 215 ± 99 s; P ≤ 0.01) and had a 17% longer peak walking time (467 ± 223 s vs. 533 ± 233 s; P ≤ 0.05) following BR vs. PL. Gastrocnemius tissue fractional O(2) extraction was lower during exercise following BR (7.3 ± 6.2 vs. 10.4 ± 6.1 arbitrary units; P ≤ 0.01). Diastolic blood pressure was lower in the BR group at rest and during CPX testing (P ≤ 0.05). These findings support the hypothesis that NO(2)(-)-related NO signaling increases peripheral tissue oxygenation in areas of hypoxia and increases exercise tolerance in PAD.

Preventing sarcopenic obesity among breast cancer patients who receive adjuvant chemotherapy: results of a feasibility study.

PURPOSE: Weight gain is a common side effect of adjuvant chemotherapy for breast cancer - a side effect that decreases quality of life and also may decrease both disease-free and overall survival. This weight gain also is unique, since patients lose lean body mass while they gain weight. These body composition changes become apparent within six months of diagnosis. METHODS: We explored whether a clinic-based exercise program, which promoted a specialized program of strength training, aerobic activity and a healthful (