Interval training in men at risk for insulin resistance.

We compared 3 months of eucaloric (12 kcal/kg/wk) steady state aerobic training (AER) to interval training (INT) in men at risk for insulin resistance. Primary outcomes included oral glucose tolerance testing (OGTT) and HOMA-IR 24 h and 72 h after each participants last exercise session. Secondary outcomes were VO2max, anthropometry, and metabolic syndrome expressed as a summed z-score (zMS). We also performed a sub-analysis for participants entering the trial above and below the HOMA-IR study median. Mean (95% CI) AER ( - 12.81 mg/dl; - 24.7, - 1.0) and INT ( - 14.26 mg/dl; - 24.9, - 3.6) significantly improved 24 h OGTT. HOMA-IR did not improve for AER, but did for INT 24 h and 72 h post-exercise. VO2max improved similarly for both groups. Changes in body mass for INT ( - 2.29 kg; - 3.51, - 1.14), AER, ( - 1.32 kg; - 2.62, 0.58)] and percent body fat [INT, - 0.83%; - 1.62, - 0.03), AER ( - 0.17%; - 1.07, 0.06)] were only significant for INT. When examined as a full cohort, zMS improved for both groups. Upon HOMA-IR stratification, only high HOMA-IR AER showed significant improvements, while both low and high INT HOMA-IR participants demonstrated significant reductions (P<0.05). Eucaloric AER and INT appear to affect fasting glucose, OGTT and VO2max similarly, while INT may have a greater impact on HOMA-IR and zMS.

Acute high-intensity interval exercise reduces the postprandial glucose response and prevalence of hyperglycaemia in patients with type 2 diabetes.

High-volume endurance exercise (END) improves glycaemic control in type 2 diabetes (T2D) but many individuals cite 'lack of time' as a barrier to regular participation. High-intensity interval training (HIT) is a time-efficient method to induce physiological adaptations similar to END, but little is known regarding the effect of HIT in T2D. Using continuous glucose monitoring (CGM), we examined the 24-h blood glucose response to one session of HIT consisting of 10 × 60 s cycling efforts at ~90% maximal heart rate, interspersed with 60 s rest. Seven adults with T2D underwent CGM for 24-h on two occasions under standard dietary conditions: following acute HIT and on a non-exercise control day (CTL). HIT reduced hyperglycaemia measured as proportion of time spent above 10 mmol/l (HIT: 4.5 ± 4.4 vs. CTL: 15.2 ± 12.3%, p = 0.04). Postprandial hyperglycaemia, measured as the sum of post-meal areas under the glucose curve, was also lower after HIT vs. CTL (728 ± 331 vs. 1142 ± 556 mmol/l·9 h, p = 0.01). These findings highlight the potential for HIT to improve glycaemic control in T2D.

What's new since Hippocrates? Preventing type 2 diabetes by physical exercise and diet.

Since the work of Eriksson and Lindgärde, published over two decades ago (Diabetologia 1991;34:891-898), we have known that type 2 diabetes can be prevented or delayed by supervised lifestyle interventions (physical exercise and diet modification) in persons at risk of the disease. Here we discuss a novel, time-efficient approach to physical exercise prescription, low-volume, high-intensity interval training (LVHIT), and its efficacy for inducing a range of health benefits in a variety of populations at risk of inactivity-related diseases. We look to the future and suggest that current guidelines for exercise may need to be revised to include different training techniques to deliver the optimum exercise prescription. Indeed, we predict that subsequent exercise guidelines will include LVHIT as part of a comprehensive 'fitness menu' that allows individuals to select the exercise regimen that best fulfils their medical needs, is suited to their lifestyle and daily time restraints, and meets their personal goals.

Oxidative stress, inflammation, and muscle soreness in an 894-km relay trail run.

We describe the effects of multi-day relay trail running on muscle soreness and damage, and systemic immune, inflammatory, and oxidative responses. 16 male and 4 female athletes ran 894 km in 47 stages over 95 h, with mean (SD) 6.4 (1.0) stages per athlete and 19.0 (1.7) km per stage. We observed post-pre run increases in serum creatine kinase (qualified effect size extremely large, p = 0.002), IL-6 (extremely large, p < 0.001), urinary 8-isoprostane/creatinine (extremely large, p = 0.04), TNF-α (large, p = 0.002), leukocyte count (very large, p < 0.0001) and neutrophil fraction (very large, p < 0.001); and reductions in hemoglobin (moderate, p < 0.001), hematocrit (moderate, p < 0.001), and lymphocyte fraction (trivial, p < 0.001). An increase in ORAC total antioxidant capacity (TAC, small, p = 0.3) and decrease in urinary 8-OHdG/creatinine (small, p = 0.1) were not statistically significant. During the run, muscle soreness was most frequent in the quadriceps. The threshold for muscle pain (pain-pressure algometry) in the vastus lateralis and gastrocnemius was lower post-run (small, p = 0.04 and 0.03). Average running speed was correlated with algometer pain and leukocyte count (large, r = 0.52), and TAC was correlated with IL-6 (very large, r = 0.76) and 8-isoprostane/creatinine (very large, r = -0.72). Multi-day stage-racing increases inflammation, lipid peroxidation, muscle damage and soreness without oxidative DNA damage. High TAC is associated with reduced exercise-induced lipid peroxidation, but is not related to immune response or muscle damage.

Four weeks one-leg training and high fat diet does not alter PPARalpha protein or mRNA expression in human skeletal muscle.

UNLABELLED: Fatty acid metabolism is influenced by training and diet with exercise training mediating this through activation of nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in skeletal muscle. This study investigated the effect of training and high fat or normal diet on PPARalpha expression in human skeletal muscle. Thirteen men trained one leg (T) four weeks (31.5 h in total), while the other leg (UT) served as control. During the 4 weeks six subjects consumed high fat (FAT) diet and seven subjects maintained a normal (CHO) diet. Biopsies were obtained from vastus lateralis muscle in both legs before and after training. After the biopsy, one-leg extension exercise was performed in random order with both legs 30 min at 95% of workload max. A training effect was evident as citrate synthase activity increased (P < 0.05) by 15% in the trained, but not the control leg in both groups. During exercise respiratory exchange ratio was lower in FAT (0.86 +/- 0.01, 0.83 +/- 0.01, mean +/- SEM) than CHO (0.96 +/- 0.02, 0.94 +/- 0.03) and in UT than T legs, respectively. The PPARalpha protein (144 +/- 44, 104 +/- 28, 79 +/- 15, 79 +/- 14, % of pre level) and PPARalpha mRNA (69 +/- [2, 2], 78 +/- [7, 6], 92 +/- [22, 18], 106 +/- [21, 18], % of pre level, geometric mean +/- SEM) expression remained unchanged by diet and training in FAT (UT, T) and CHO (UT, T), respectively. After the training and diet CS, HAD, PPARalpha, UCP2, UCP3 and mFABP mRNA content remained unchanged, whereas GLUT4 mRNA was lower in both groups and LDHA mRNA was lower (P < 0.05) only in FAT. IN CONCLUSION: 4 weeks one leg knee extensor training did not affect PPARalpha protein or mRNA expression. Furthermore, higher fat oxidation during exercise after fat rich diet was not accompanied by an increased PPARalpha protein or mRNA expression after 4 weeks.

Myoadenylate deaminase deficiency does not affect muscle anaplerosis during exhaustive exercise in humans.

1. Myoadenylate deaminase (AMPD) deficiency is present in 1--2 % of the population. In theory, this deficiency may alter exercise energy metabolism by impairing the purine nucleotide cycle (PNC) and reducing tricarboxylic acid (TCA) cycle anaplerosis. The role of the PNC in TCA cycle anaplerosis is still a debated issue in physiology. Using patients with the AMPD1 mutation will allow a human 'knockout' approach to answering this question. 2. Muscle AMPD activity and genotype (whole blood AMPD1 analysis) was used to classify participants into three groups: n = 3 with absence of AMPD activity and -/- AMPD1 genotype (homozygous); n = 4 with less than 50 % normal AMPD activity and +/- genotype (heterozygous) and n = 12 with normal AMPD activity and +/+ genotype (control). Biopsies were taken from the vastus lateralis muscle before and after incremental cycle ergometry exercise to exhaustion. The muscle biopsies were analysed for AMPD activity, purine nucleotides/nucleosides and bases, creatine, phosphocreatine, amino acids, and the TCA cycle intermediates malate, citrate and fumarate. 3. Time to exhaustion on the cycle ergometer was not different between groups. Muscle adenosine monophosphate increased significantly with exercise for homozygous subjects as compared with the other groups (P < 0.05). Inosine monophosphate increased significantly after exercise for control (P < 0.05) but not for the homozygous subjects. There were no other between-group differences for any other measured variables. 4. In summary, complete and partial muscle AMPD deficiency did not affect TCA cycle anaplerosis, phosphocreatine hydrolysis, energy charge or exercise performance.

Regulation of skeletal muscle amino acid metabolism during exercise.

The contribution of amino acid oxidation to total energy expenditure is negligible during short-term intense exercise and accounts for 3-6% of the total adenosine triphosphate supplied during prolonged exercise in humans. While not quantitatively important in terms of energy supply, the intermediary metabolism of several amino acids-notably glutamate, alanine, and the branched-chain amino acids-affects other metabolites, including the intermediates within the tricarboxylic acid (TCA) cycle. Glutamate appears to be a key substrate for the rapid increase in muscle TCA cycle intermediates (TCAI) that occurs at the onset of moderate to intense exercise, due to a rightward shift of the reaction catalyzed by alanine aminotransferase (glutamate + pyruvate <==> alanine + 2-oxoglutarate). The pool of muscle TCAI declines during prolonged exercise, and this has been attributed to an increase in leucine oxidation that relies on one of the TCAI. However, this mechanism does not appear to be quantitatively important due of the relatively low maximal activity of branched-chain oxoacid dehydrogenase, the key enzyme involved. It has been suggested that an increase in TCAI is necessary to attain high rates of aerobic energy production and that a decline in TCAI may be a causative factor in local muscle fatigue. These topics remain controversial, but recent evidence suggests that changes in TCAI during exercise are unrelated to oxidative energy provision in skeletal muscle.

Nutritional supplementation and resistance exercise: what is the evidence for enhanced skeletal muscle hypertrophy?

Many athletes and recreational weightlifters believe that dietary manipulations' either following a single bout of resistance exercise or during habitual training may augment the normal gains in muscle fibre hypertrophy. Very few studies, however, have directly examined the effect of nutritional supplementation on muscle protein metabolism after resistance exercise. Ingestion of an amino acid and/or carbohydrate solution during the initial hours following a single bout of resistance exercise promotes an acute increase in protein net balance compared to the fasted state. The precise mechanism involved has not been elucidated but seems related to an increased availability of intracellular amino acids and/or an increase in plasma insulin concentration. As a practical recommendation, therefore, postexercise feeding appears to be very important. Recent evidence suggests that creatine supplementation in conjunction with resistance training may elicit larger increases in muscle fiber cross-sectional area compared to training alone. This intervention may be most beneficial in persons with "compromised" skeletal muscle.

Myofibrillar disruption following acute concentric and eccentric resistance exercise in strength-trained men.

We have previously quantified the extent of myofibrillar disruption which occurs following an acute bout of resistance exercise in untrained men, however the response of well-trained subjects is not known. We therefore recruited six strength-trained men, who ceased training for 5 days and then performed 8 sets of 8 uni-lateral repetitions, using a load equivalent to 80% of their concentric (Con) 1-repetition maximum. One arm performed only Con actions by lifting the weight and the other arm performed only eccentric actions (Ecc) by lowering it. Needle biopsy samples were obtained from biceps brachii of each arm approximately 21 h following exercise, and at baseline (i.e., after 5 days without training), and subsequently analyzed using electron microscopy to quantify myofibrillar disruption. A greater (P < or = 0.05) proportion of disrupted fibres was found in the Ecc arm (45 +/- 11%) compared with baseline values (4 +/- 2%), whereas fibre disruption in the Con arm (27 +/- 4%) was not different (P > 0.05) from baseline values. The proportion of disrupted fibres and the magnitude of disruption (quantified by sarcomere counting) was considerably less severe than previously observed in untrained subjects after an identical exercise bout. Mixed muscle protein synthesis, assessed from approximately 21-29 h post-exercise, was not different between the Con- and Ecc-exercised arms. We conclude that the Ecc phase of resistance exercise is most disruptive to skeletal muscle and that training attenuates the severity of this effect. Moreover, it appears that fibre disruption induced by habitual weightlifting exercise is essentially repaired after 5 days of inactivity in trained men.

Endurance exercise training attenuates leucine oxidation and BCOAD activation during exercise in humans.

We studied the effects of a 38-day endurance exercise training program on leucine turnover and substrate metabolism during a 90-min exercise bout at 60% peak O(2) consumption (VO(2 peak)) in 6 males and 6 females. Subjects were studied at both the same absolute (ABS) and relative (REL) exercise intensities posttraining. Training resulted in a significant increase in whole body VO(2 peak) and skeletal muscle citrate synthase (CS; P < 0.001), complex I-III (P < 0.05), and total branched-chain 2-oxoacid dehydrogenase (BCOAD; P < 0.001) activities. Leucine oxidation increased during exercise for the pretraining trial (PRE, P < 0.001); however, there was no increase for either the ABS or REL posttraining trial. Leucine oxidation was significantly lower for females at all time points during rest and exercise (P < 0.01). The percentage of BCOAD in the activated state was significantly increased after exercise for both the PRE and REL exercise trials, with the increase in PRE being greater (P < 0.001) compared with REL (P < 0.05). Females oxidized proportionately more lipid and less carbohydrate during exercise compared with males. In conclusion, we found that 38 days of endurance exercise training significantly attenuated both leucine oxidation and BCOAD activation during 90 min of endurance exercise at 60% VO(2 peak) for both ABS and REL exercise intensities. Furthermore, females oxidize proportionately more lipid and less carbohydrate compared with males during endurance exercise.

Anaplerosis of the citric acid cycle: role in energy metabolism of heart and skeletal muscle.

Efficient energy transfer in heart and skeletal muscle requires a series of moiety-conserved cycles. The intermediaries of the metabolic cycles are finely regulated to maintain a dynamic state of equilibrium. In heart muscle, depletion of the citric acid cycle (TCA cycle) through a block of 2-oxoglutarate dehydrogenase results in a rapid decline of contractile function, which is reversed by the addition of substrates promoting flux through the carboxylating enzymes, malic enzyme, pyruvate carboxylase and propionyl-CoA carboxylase. Anaplerosis describes a pathway, which replenishes a metabolic cycle. We show that enzymes for anaplerosis of the TCA cycle are expressed in heart and skeletal muscles. The role of anaplerosis of the TCA cycle in skeletal muscle is not entirely clear, but there is substantial evidence for its operational control during exercise. While the anaplerotic flux of carbon into the TCA cycle exceeds the removal of cycle intermediates, this process is only transient and reverses with prolonged exercise. It remains to be determined, however, whether the initial increase in TCA cycle intermediates is obligatory in order to attain high rates of TCA cycle flux, or primarily reflects a mass action phenomenon owing to increased substrate availability for anaplerotic pathways.

Glutamate ingestion: the plasma and muscle free amino acid pools of resting humans.

Monosodium glutamate (MSG) ingestion is known to increase plasma glutamate concentration, and MSG infusion stimulates insulin secretion. We investigated the impact of MSG ingestion on both the plasma and intramuscular amino acid pools. Nine postprandial adults ingested MSG (150 mg/kg) and rested for 105 min. Venous blood was sampled preingestion and then every 15 min; vastus lateralis muscle biopsies were taken preingestion and at 45, 75, and 105 min postingestion. Venous plasma glutamate and aspartate concentrations increased (P

Low glycogen and branched-chain amino acid ingestion do not impair anaplerosis during exercise in humans.

We examined the hypothesis that increasing the rate of branched-chain amino acid (BCAA) oxidation, during conditions of low glycogen availability, reduces the level of muscle tricarboxylic acid cycle intermediates (TCAI) by placing a carbon "drain" on the cycle at the level of 2-oxoglutarate. Six men cycled at approximately 70% of maximal oxygen uptake for 15 min under two conditions: 1) low preexercise muscle glycogen (placebo) and 2) low glycogen combined with BCAA ingestion. We have previously shown that BCAA ingestion increased the activity of branched-chain oxoacid dehydrogenase, the rate-limiting enzyme for BCAA oxidation in muscle, compared with low glycogen alone [M. L. Jackman, M. J. Gibala, E. Hultman, and T. E. Graham. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E233-E238, 1997]. Muscle glycogen concentration was 185 +/- 22 and 206 +/- 22 mmol/kg dry wt at rest for the placebo and BCAA-supplemented trials, respectively, and decreased to 109 +/- 18 and 96 +/- 10 mmol/kg dry wt after exercise. The net increase in the total concentration of six measured TCAI ( approximately 95% of TCAI pool) during exercise was not different between trials (3.97 +/- 0. 34 vs. 3.88 +/- 0.34 mmol/kg dry wt for the placebo and BCAA trials, respectively). Muscle 2-oxoglutarate concentration decreased from approximately 0.05 at rest to approximately 0.03 mmol/kg dry wt after exercise in both trials. The magnitude of TCAI pool expansion in both trials was similar to that seen previously in subjects who performed an identical exercise bout after a normal mixed diet [M. J. Gibala, M. A. Tarnopolsky, and T. E. Graham. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E239-E244, 1997]. These data suggest that increasing the rate of BCAA oxidation has no measurable effect on muscle TCAI during exercise with low glycogen in humans. Moreover, it appears that low resting glycogen per se does not impair the increase in TCAI during moderate exercise.

PDH activation by dichloroacetate reduces TCA cycle intermediates at rest but not during exercise in humans.

We hypothesized that dichloroacetate (DCA), which stimulates the pyruvate dehydrogenase complex (PDH), would attenuate the increase in muscle tricarboxylic acid cycle intermediates (TCAI) during exercise by increasing the oxidative disposal of pyruvate and attenuating the flux through anaplerotic pathways. Six subjects were infused with either saline (Con) or DCA (100 mg/kg body mass) and then performed a moderate leg kicking exercise for 15 min, followed immediately by intense exercise until exhaustion (Exh; approximately 4 min). Resting active fraction of PDH (PDH(a)) was markedly increased (P

Anaplerosis of the tricarboxylic acid cycle in human skeletal muscle during exercise. Magnitude, sources, and potential physiological significance.

In comparison to cardiac tissue, relatively few data are available regarding the concentrations of tricarboxylic acid cycle intermediates (TCAI) and the potential influence of TCAI pool size on the regulation of cycle flux in mammalian skeletal muscle. However, recent human exercise studies have confirmed the fundamental observation made in electrically-stimulated rodent muscle that moderate to intense contraction results in a net accumulation of TCAI. The increase in TCAI pool size, termed "anaplerosis," appears exponentially related to work intensity, although the relative changes in the individual cycle intermediates differ markedly. While a number of mechanisms could potentially contribute to the increase in TCAI, the reaction catalyzed by alanine aminotransferase appears primarily responsible for anaplerosis at the onset of exercise in humans. The expansion of the TCAI pool has been suggested to be important for aerobic energy provision, and various theories have been proposed which link the total concentration of TCAI with the capacity for TCA cycle flux during exercise. However, despite the recent advances which have been made with regard to the magnitude and potential source of TCAI expansion in humans, our understanding of the physiological significance of anaplerosis is limited. Indeed, it remains speculative whether the increase in TCAI pool size represents an important regulatory signal or is simply a consequence of the huge increase in metabolic flux which occurs during exercise.

Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise.

We examined the relationship between tricarboxylic acid (TCA) cycle intermediate (TCAI) pool size, TCA cycle flux (calculated from leg O2 uptake), and pyruvate dehydrogenase activity (PDHa) in human skeletal muscle. Six males performed moderate leg extensor exercise for 10 min, followed immediately by intense exercise until exhaustion (3.8 +/- 0.5 min). The sum of seven measured TCAI (SigmaTCAI) increased (P

Anaplerotic processes in human skeletal muscle during brief dynamic exercise.

1. This study examined changes in tricarboxylic acid cycle intermediates (TCAIs) in human skeletal muscle during 5 min of dynamic knee extensor exercise (approximately 80% of maximum workload) and following 2 min of recovery. 2. The sum of the seven measured TCAIs (sigma TCAIs) increased from 1.10 +/- 0.08 mmol (kg dry weight)-1 at rest to 3.12 +/- 0.24, 3.86 +/- 0.35 and 4.33 +/- 0.30 mmol (kg dry weight)-1 after 1, 3 and 5 min of exercise, respectively (P < or = 0.05): The sigma TCAIs after 2 min of recovery (3.74 +/- 0.43 mmol (kg dry weight)-1) was not different compared with 5 min of exercise. 3. The rapid increase in sigma TCAIs during exercise was primarily mediated by large changes in succinate, malate and fumarate. These three intermediates accounted for > 90% of the net increase in sigma TCAIs during the first minute of contraction. 4. Intramuscular alanine increased after 1 min of exercise by an amount similar to the increase in the sigma TCAIs (2.33 mmol (kg dry weight)-1) (P < or = 0.05). Intramuscular pyruvate was also higher (P < or = 0.05) during exercise, while intramuscular glutamate decreased by approximately 50% within 1 min and remained low despite an uptake from the circulation (P < or = 0.05). 5. The calculated net release plus estimated muscle accumulation of ammonia after 1 min of exercise (approximately 60 mumol (kg wet weight)-1) indicated that only a minor portion of the increase in sigma TCAIs could have been mediated through the purine nucleotide cycle and/or glutamate dehydrogenase reaction. 6. It is concluded that the close temporal relationship between the increase in sigma TCAIs and changes in glutamate, alanine and pyruvate metabolism suggests that the alanine aminotransferase reaction is the most important anaplerotic process during the initial minutes of contraction in human skeletal muscle.

Nutritional status affects branched-chain oxoacid dehydrogenase activity during exercise in humans.

We examined the effect of glycogen availability and branched-chain amino acid (BCAA) supplementation on branched-chain oxoacid dehydrogenase (BCOAD) activity during exercise. Six subjects cycled at approximately 75% of their maximal oxygen uptake to exhaustion on three occasions under different preexercise conditions: 1) low muscle glycogen (LOW), 2) low muscle glycogen plus BCAA supplementation (LOW+BCAA), and 3) high muscle glycogen (CON). The LOW trial was performed first, followed by the other two conditions in random order, and biopsies for all trials were obtained at rest, after 15 min of exercise (15 min), and at the point of exhaustion during the LOW trial (49 min). BCOAD activity was not different among the three conditions at rest; however, at 15 min BCOAD activity was higher (P < or = 0.05) for the LOW (31 +/- 5%) and LOW+BCAA (43 +/- 11%) conditions compared with CON (12 +/- 1%). BCOAD activity at 49 min was not different from respective values at 15 min for any condition. These data indicate that BCOAD is rapidly activated during submaximal exercise under conditions associated with low carbohydrate availability. However, there was no relationship between BCOAD activity and glycogen concentration or net glycogenolysis, which suggests that factors other than glycogen availability are important for BCOAD regulation during exercise in humans.