Ergogenic properties of metformin in simulated high altitude.

Metformin augments glucose/glycogen regulation and may acutely promote fatigue resistance during high-intensity exercise. In hypobaric environments, such as high altitude, the important contribution of carbohydrates to physiological function is accentuated as glucose/glycogen dependence is increased. Because hypoxia/hypobaria decreases insulin sensitivity, replenishing skeletal muscle glycogen in high altitude becomes challenging and subsequent physical performance may be compromised. We hypothesized that in conditions where glycogen repletion was critical to physical outcomes, metformin would attenuate hypoxia-mediated decrements in exercise performance. On three separate randomly ordered occasions, 13 healthy men performed glycogen-depleting exercise and ingested a low-carbohydrate dinner (1200 kcals, <10% carbohydrate). The next morning, in either normoxia or hypoxia (FiO2 =0.15), they ingested a high-carbohydrate breakfast (1225 kcals, 70% carbohydrate). Placebo (719 mg maltodextrin) or metformin (500 mg BID) was consumed 3 days prior to each hypoxia visit. Subjects completed a 12.5 km cycle ergometer time trial 3.5 hours following breakfast. Hypoxia decreased resting and exercise oxyhemoglobin saturation (P<.001). Neither hypoxia nor metformin affected the glucose response to breakfast (P=.977), however, compared with placebo, metformin lowered insulin concentration in hypoxia 45 minutes after breakfast (64.1±6.6 µU/mL vs 48.5±7.8 µU/mL; mean±SE; P<.001). Post-breakfast, pre-exercise vastus lateralis glycogen content increased in normoxia (+33%: P=.025) and in hypoxia with metformin (+81%; P=.006), but not in hypoxia with placebo (+27%; P=.167). Hypoxia decreased time trial performance compared with normoxia (P<.01). This decrement was similar with placebo (+2.6±0.8 minutes) and metformin (+1.6±0.3 minutes). These results indicate that metformin promotes glycogen synthesis but not endurance exercise performance in healthy men exposed to simulated high altitude.

Concurrent Beet Juice and Carbohydrate Ingestion: Influence on Glucose Tolerance in Obese and Nonobese Adults.

Insulin resistance and obesity are characterized by low nitric oxide (NO) bioavailability. Insulin sensitivity is improved with stimulation of NO generating pathways. Consumption of dietary nitrate (NO3-) increases NO formation, via NO3- reduction to nitrite (NO2-) by oral bacteria. We hypothesized that acute dietary nitrate (beet juice) ingestion improves insulin sensitivity in obese but not in nonobese adults. 12 nonobese (body mass index: 26.3 ± 0.8 kg/m2 (mean ± SE)) and 10 obese adults (34.0 ± 0.8 kg/m2) ingested beet juice, supplemented with 25 g of glucose (carbohydrate load: 75 g), with and without prior use of antibacterial mouthwash to inhibit NO3- reduction to NO2-. Blood glucose concentrations after beet juice and glucose ingestion were greater in obese compared with nonobese adults at 60 and 90 minutes (P = 0.004). Insulin sensitivity, as represented by the Matsuda Index (where higher values reflect greater insulin sensitivity), was lower in obese compared with nonobese adults (P = 0.009). Antibacterial mouthwash rinsing decreased insulin sensitivity in obese (5.7 ± 0.7 versus 4.9 ± 0.6) but not in nonobese (8.1 ± 1.0 versus 8.9 ± 0.9) adults (P = 0.048). In conclusion, insulin sensitivity was improved in obese but not in nonobese adults following coingestion of beet juice and glucose when oral bacteria nitrate reduction was not inhibited. Obese adults may benefit from ingestion of healthy nitrate-rich foods during meals.

Liposomal-encapsulated Ascorbic Acid: Influence on Vitamin C Bioavailability and Capacity to Protect Against Ischemia-Reperfusion Injury.

Intravenous administration of vitamin C has been shown to decrease oxidative stress and, in some instances, improve physiological function in adult humans. Oral vitamin C administration is typically less effective than intravenous, due in part to inferior vitamin C bioavailability. The purpose of this study was to determine the efficacy of oral delivery of vitamin C encapsulated in liposomes. On 4 separate randomly ordered occasions, 11 men and women were administered an oral placebo, or 4 g of vitamin C via oral, oral liposomal, or intravenous delivery. The data indicate that oral delivery of 4 g of vitamin C encapsulated in liposomes (1) produces circulating concentrations of vitamin C that are greater than unencapsulated oral but less than intravenous administration and (2) provides protection from ischemia-reperfusion-mediated oxidative stress that is similar to the protection provided by unencapsulated oral and intravenous administrations.

Methazolamide Plus Aminophylline Abrogates Hypoxia-Mediated Endurance Exercise Impairment.

In hypoxia, endurance exercise performance is diminished; pharmacotherapy may abrogate this performance deficit. Based on positive outcomes in preclinical trials, we hypothesized that oral administration of methazolamide, a carbonic anhydrase inhibitor, aminophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, and/or methazolamide combined with aminophylline would attenuate hypoxia-mediated decrements in endurance exercise performance in humans. Fifteen healthy males (26 ± 5 years, body-mass index: 24.9 ± 1.6 kg/m(2); mean ± SD) were randomly assigned to one of four treatments: placebo (n = 9), methazolamide (250 mg; n = 10), aminophylline (400 mg; n = 9), or methazolamide (250 mg) with aminophylline (400 mg; n = 8). On two separate occasions, the first in normoxia (FIO2 = 0.21) and the second in hypoxia (FIO2 = 0.15), participants sat for 4.5 hours before completing a standardized exercise bout (30 minutes, stationary cycling, 100 W), followed by a 12.5-km time trial. The magnitude of time trial performance decrement in hypoxia versus normoxia did not differ between placebo (+3.0 ± 2.7 minutes), methazolamide (+1.4 ± 1.7 minutes), and aminophylline (+1.8 ± 1.2 minutes), all with p > 0.09; however, the performance decrement in hypoxia versus normoxia with methazolamide combined with aminophylline was less than placebo (+0.6 ± 1.5 minutes; p = 0.01). This improvement may have been partially mediated by increased SpO2 in hypoxia with methazolamide combined with aminophylline compared with placebo (73% ± 3% vs. 79% ± 6%; p < 0.02). In conclusion, coadministration of methazolamide and aminophylline may promote endurance exercise performance during a sojourn at high altitude.

The Effects of Sympathetic Inhibition on Metabolic and Cardiopulmonary Responses to Exercise in Hypoxic Conditions.

OBJECTIVE: Pre-exertion skeletal muscle glycogen content is an important physiological determinant of endurance exercise performance: low glycogen stores contribute to premature fatigue. In low-oxygen environments (hypoxia), the important contribution of carbohydrates to endurance performance is further enhanced as glucose and glycogen dependence is increased; however, the insulin sensitivity of healthy adult humans is decreased. In light of this insulin resistance, maintaining skeletal muscle glycogen in hypoxia becomes difficult, and subsequent endurance performance is impaired. Sympathetic inhibition promotes insulin sensitivity in hypoxia but may impair hypoxic exercise performance, in part due to suppression of cardiac output. Accordingly, we tested the hypothesis that hypoxic exercise performance after intravenous glucose feeding in a low-oxygen environment will be attenuated when feeding occurs during sympathetic inhibition. METHODS: On 2 separate occasions, while breathing a hypoxic gas mixture, 10 healthy men received 1 hour of parenteral carbohydrate infusion (20% glucose solution in saline; 75 g), after which they performed stationary cycle ergometer exercise (~65% maximal oxygen uptake) until exhaustion. Forty-eight hours before 1 visit, chosen randomly, sympathetic inhibition via transdermal clonidine (0.2 mg/d) was initiated. RESULTS: The mean time to exhaustion after glucose feeding both with and without sympathetic inhibition was not different (22.7 ± 5.4 minutes vs 23.5 ± 5.1 minutes; P = .73). CONCLUSIONS: Sympathetic inhibition protects against hypoxia-mediated insulin resistance without influencing subsequent hypoxic endurance performance.

Regulators of human white adipose browning: evidence for sympathetic control and sexual dimorphic responses to sprint interval training.

The conversion of white adipose to the highly thermogenic beige adipose tissue has been proposed as a potential strategy to counter the unfavorable consequences of obesity. Three regulators of this conversion have recently emerged but information regarding their control is limited, and contradictory. We present two studies examining the control of these regulators. Study 1: In 10 young men, the plasma concentrations of irisin and fibroblast growth factor 21 (FGF21) were determined prior to and during activation of the sympathetic nervous system via hypoxic gas breathing (FIO2 = 0.11). The measurements were performed twice, once with and once without prior/concurrent sympathetic inhibition via transdermal clonidine administration. FGF21 was unaffected by basal sympathetic inhibition (338±113 vs. 295±80 pg/mL; P = 0.43; mean±SE), but was increased during hypoxia mediated sympathetic activation (368±135); this response was abrogated (P = 0.035) with clonidine (269±93). Irisin was unaffected by sympathetic inhibition and/or hypoxia (P>0.21). Study 2: The plasma concentration of irisin and FGF21, and the skeletal muscle protein content of fibronectin type III domain containing 5 (FNDC5) was determined in 19 young adults prior to and following three weeks of sprint interval training (SIT). SIT decreased FGF21 (338±78 vs. 251±36; P = 0.046) but did not affect FNDC5 (P = 0.79). Irisin was decreased in males (127±18 vs. 90±23 ng/mL; P = 0.045) and increased in females (139±14 vs. 170±18). Collectively, these data suggest a potential regulatory role of acute sympathetic activation pertaining to the browning of white adipose; further, there appears to be a sexual dimorphic response of irisin to SIT.

Greater muscle protein synthesis and mitochondrial biogenesis in males compared with females during sprint interval training.

Improved endurance exercise performance in adult humans after sprint interval training (SIT) has been attributed to mitochondrial biogenesis. However, muscle protein synthesis (MPS) and mitochondrial biogenesis during SIT have not been measured, nor have sex-specific differences. We hypothesized that males and females would have similar rates of MPS, mitochondrial biogenesis, and synthesis of individual proteins during SIT. Deuterium oxide (D2O) was orally administered to 21 adults [11 male, 10 female; mean age, 23±1 yr; body mass index (BMI), 22.8±0.6 kg/m(2); mean± SE] for 4 wk, to measure protein synthesis rates while completing 9 sessions of 4-8 bouts of 30 s duration on a cycle ergometer separated by 4 min of active recovery. Samples of the vastus lateralis were taken before and 48 h after SIT. SIT increased maximum oxygen uptake (VO(2max), males 43.4±2.1-44.0±2.3; females 39.5±0.9-42.5±1.3 ml/kg/min; P=0.002). MPS was greater in the males than in the females in the mixed (~150%; P < 0.001), cytosolic (~135%; P=0.038), and mitochondrial (~135%; P=0.056) fractions. The corresponding ontological clusters of individual proteins were significantly greater in the males than in the females (all P<0.00001). For the first time, we document greater MPS and mitochondrial biogenesis during SIT in males than in females and describe the synthetic response of individual proteins in humans during exercise training.

Total daily energy expenditure is increased following a single bout of sprint interval training.

REGULAR ENDURANCE EXERCISE IS AN EFFECTIVE STRATEGY FOR HEALTHY WEIGHT MAINTENANCE, MEDIATED VIA INCREASED TOTAL DAILY ENERGY EXPENDITURE (TDEE), AND POSSIBLY AN INCREASE IN RESTING METABOLIC RATE (RMR: the single largest component of TDEE). Sprint interval training (SIT) is a low-volume alternative to endurance exercise; however, the utility of SIT for healthy weight maintenance is less clear. In this regard, it is feasible that SIT may evoke a thermogenic response above and beyond the estimates required for prevention of weight gain (i.e., >200-600 kJ). The purpose of these studies was to investigate the hypotheses that a single bout of SIT would increase RMR and/or TDEE. Study 1: RMR (ventilated hood) was determined on four separate occasions in 15 healthy men. Measurements were performed over two pairs of consecutive mornings; each pair was separated by 7 days. Immediately following either the first or third RMR measurement (randomly assigned) subjects completed a single bout of SIT (cycle ergometer exercise). RMR was unaffected by a single bout of SIT (7195 ± 285 kJ/day vs. 7147 ± 222, 7149 ± 246 and 6987 ± 245 kJ/day (mean ± SE); P = 0.12). Study 2: TDEE (whole-room calorimeter) was measured in 12 healthy men, on two consecutive days, one of which began with a single bout of SIT (random order). Sprint exercise increased TDEE in every research participant (9169 ± 243 vs. 10,111 ± 260 kJ/day; P < 0.0001); the magnitude of increase was 946 ± 62 kJ/day (∼10%). These data provide support for SIT as a strategy for increasing TDEE, and may have implications for healthy body weight maintenance.