Ole Johan Kemi

Aerobic Interval Training Versus Continuous Moderate Exercise as a Treatment for the Metabolic Syndrome A Pilot Study

Background— Individuals with the metabolic syndrome are 3 times more likely to die of heart disease than healthy counterparts. Exercise training reduces several of the symptoms of the syndrome, but the exercise intensity that yields the maximal beneficial adaptations is in dispute. We compared moderate and high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with the metabolic syndrome. Methods and Results— Thirty-two metabolic syndrome patients (age, 52.3±3.7 years; maximal oxygen uptake [&OV0312;o2max], 34 mL · kg−1 · min−1) were randomized to equal volumes of either moderate continuous moderate exercise (CME; 70% of highest measured heart rate [Hfmax]) or aerobic interval training (AIT; 90% of Hfmax) 3 times a week for 16 weeks or to a control group. &OV0312;o2max increased more after AIT than CME (35% versus 16%; P<0.01) and was associated with removal of more risk factors that constitute the metabolic syndrome (number of factors: AIT, 5.9 before versus 4.0 after; P<0.01; CME, 5.7 before versus 5.0 after; group difference, P<0.05). AIT was superior to CME in enhancing endothelial function (9% versus 5%; P<0.001), insulin signaling in fat and skeletal muscle, skeletal muscle biogenesis, and excitation-contraction coupling and in reducing blood glucose and lipogenesis in adipose tissue. The 2 exercise programs were equally effective at lowering mean arterial blood pressure and reducing body weight (−2.3 and −3.6 kg in AIT and CME, respectively) and fat. Conclusions— Exercise intensity was an important factor for improving aerobic capacity and reversing the risk factors of the metabolic syndrome. These findings may have important implications for exercise training in rehabilitation programs and future studies.

High-Intensity Interval Training to Maximize Cardiac Benefits of Exercise Training?

We hypothesized that high-intensity aerobic interval training results in a greater beneficial adaptation of the heart compared with that observed after low-to-moderate exercise intensity. This is supported by recent epidemiological, experimental, and clinical studies. Cellular and molecular mechanisms of myocardial adaptation to exercise training are discussed in this review.

Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy

Cardiomyocyte hypertrophy differs according to the stress exerted on the myocardium. While pressure overload‐induced cardiomyocyte hypertrophy is associated with depressed contractile function, physiological hypertrophy after exercise training associates with preserved or increased inotropy. We determined the activation state of myocardial Akt signaling with downstream substrates and fetal gene reactivation in exercise‐induced physiological and pressure overload‐induced pathological hypertrophies. C57BL/6J mice were either treadmill trained for 6 weeks, 5 days/week, at 85–90% of maximal oxygen uptake (VO2max), or underwent transverse aortic constriction (TAC) for 1 or 8 weeks. Total and phosphorylated protein levels were determined with SDS‐PAGE, and fetal genes by real‐time RT‐PCR. In the physiologically hypertrophied heart after exercise training, total Akt protein level was unchanged, but Akt was chronically hyperphosphorylated at serine 473. This was accompanied by activation of the mammalian target of rapamycin (mTOR), measured as phosphorylation of its two substrates: the ribosomal protein S6 kinase‐1 (S6K1) and the eukaryotic translation initiation factor‐4E binding protein‐1 (4E‐BP1). Exercise training did not reactivate the fetal gene program (β‐myosin heavy chain, atrial natriuretic factor, skeletal muscle actin). In contrast, pressure overload after TAC reactivated fetal genes already after 1 week, and partially inactivated the Akt/mTOR pathway and downstream substrates after 8 weeks. In conclusion, changes in opposite directions of the myocardial Akt/mTOR signal pathway appears to distinguish between physiological and pathological hypertrophies; exercise training associating with activation and pressure overload associating with inactivation of the Akt/mTOR pathway. J. Cell. Physiol. 214: 316–321, 2008.

Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity

AIMS The recent development of a rat model that closely resembles the metabolic syndrome allows to study the mechanisms of amelioration of the syndrome by exercise training. Here, we compared the effectiveness for reducing cardiovascular risk factors by exercise training programmes of different exercise intensities. METHODS AND RESULTS Metabolic syndrome rats were subjected to either continuous moderate-intensity exercise (CME) or high-intensity aerobic interval training (AIT). AIT was more effective than CME at reducing cardiovascular disease risk factors linked to the metabolic syndrome. Thus, AIT produced a larger stimulus than CME for increasing maximal oxygen uptake (VO(2max); 45 vs. 10%, P < 0.01), reducing hypertension (20 vs. 6 mmHg, P < 0.01), HDL cholesterol (25 vs. 0%, P < 0.05), and beneficially altering metabolism in fat, liver, and skeletal muscle tissues. Moreover, AIT had a greater beneficial effect than CME on sensitivity of aorta ring segments to acetylcholine (2.7- vs. 2.0-fold, P < 0.01), partly because of intensity-dependent effects on expression levels of nitric oxide synthase and the density of caveolae, and a greater effect than CME on the skeletal muscle Ca2+ handling (50 vs. 0%, P < 0.05). The two exercise training programmes, however, were equally effective at reducing body weight and fat content. CONCLUSION High-intensity exercise training was more beneficial than moderate-intensity exercise training for reducing cardiovascular risk in rats with the metabolic syndrome. This was linked to more superior effects on VO(2max), endothelial function, blood pressure, and metabolic parameters in several tissues. These results demonstrate that exercise training reduces the impact of the metabolic syndrome and that the magnitude of the effect depends on exercise intensity.

Interval Training Normalizes Cardiomyocyte Function, Diastolic Ca2+ Control, and SR Ca2+ Release Synchronicity in a Mouse Model of Diabetic Cardiomyopathy

Rationale: In the present study we explored the mechanisms behind excitation–contraction (EC) coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db). Objective: We determined whether 13 weeks of aerobic interval training could restore cardiomyocyte Ca2+ cycling and EC coupling. Methods and Results: Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca2+ leak, reduced synchrony of Ca2+ release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca2+ and caffeine-induced Ca2+ release. Additionally, the rate of SR Ca2+ ATPase–mediated Ca2+ uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca2+ release indicated increased Na+/Ca2+-exchanger activity. The increased SR-Ca2+ leak was attributed to increased Ca2+-calmodulin–dependent protein kinase (CaMKII&dgr;) phosphorylation, supported by the normalization of SR-Ca2+ leak on inhibition of CaMKII&dgr; (AIP). Exercise training restored contractile function associated with restored SR Ca2+ release synchronicity, T-tubule density, twitch Ca2+ amplitude, SR Ca2+ ATPase and Na+/Ca2+-exchanger activities, and SR-Ca2+ leak. The latter was associated with reduced phosphorylation of cytosolic CaMKII&dgr;. Despite normal contractile function and Ca2+ handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A inhibition (H-89) in cardiomyocytes from the exercised db/db group abolished the differences in SR-Ca2+ load when compared with the sedentary db/db mice. EC coupling changes were observed without changes in serum insulin or glucose levels, suggesting that the exercise training–induced effects are not via normalization of the diabetic condition. Conclusions: These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type.

Time-course of endothelial adaptation following acute and regular exercise

Background Regular exercise training has emerged as a powerful tool to improve endothelium-dependent vasorelaxation. However, little is known about the magnitude of change and the permanence of exercise-induced adaptations in endothelial function. Design Rats were randomized to either 6 weeks of regular exercise or one bout of exercise. Rats were then sacrificed 0, 6, 12, 24, 48, 96 or 192h post-exercise, and vascular responsiveness to acetylcholine was determined. Methods Endothelium-dependent dilation was assessed by exposure to accumulating doses of acetylcholine in ring segments of the abdominal aorta from female Sprague-Dawley rats that either exercised regularly for 6 weeks or performed a single bout of exercise. Results A single exercise session improved endothelium-dependent vasodilatation for about 48 h. Six weeks of regular exercise induced a significantly larger improvement that lasted for about 192 h. Sensitivity to acetylcholine was twofold higher in chronically trained animals than in those exposed to a single bout of exercise. The decay after a single bout of exercise was about eightfold faster than that after 6 weeks of training. Conclusion The present data extend our concept of exercise-induced adaptation of endothelium-dependent vasodilatation in two regards: (1) a single bout of exercise improves endothelium-dependent dilation for about 2 days, with peak effect after 12-24 h; (2) regular exercise further improves adaptation and increases the sensitivity to acetylcholine approximately fourfold, which slowly returns to sedentary levels within a week of detraining.

High-intensity aerobic exercise training improves the heart in health and disease.

Regular exercise training confers beneficial effects to the heart as well as to the entire body. This occurs partly because exercise training improves skeletal muscle work capacity and reduces resistance, thus increasing conductance in the peripheral circulation. More directly, exercise training also alters extrinsic modulation of the heart and improves the intrinsic pump capacity of the heart. Together, these effects allow for improved exercise capacity. Accumulating evidence suggests that the magnitude of these benefits increases proportionally with the intensity of individual exercise training sessions constituting the exercise training program. It has emerged that regular exercise training also confers beneficial effects to patients at risk for, or who have, established heart dysfunction and disease and, moreover, that exercise training may reduce the dysfunction of the heart itself and, at least, partly restore its ability to effectively function as a pump. The most recent studies in patients with established heart disease suggest that a high relative, yet aerobic, intensity of the exercise training improves the intrinsic pump capacity of the myocardium, an effect not previously believed to occur with exercise training. However, more and larger studies are needed to establish the safety and efficacy of such exercise training in patients with heart disease. Here, we consider the nature of the intensity dependence of exercise training and the causes of the improved heart function.

Aerobic Fitness Is Associated With Cardiomyocyte Contractile Capacity and Endothelial Function in Exercise Training and Detraining

Background—Physical fitness and level of regular exercise are closely related to cardiovascular health. A regimen of regular intensity-controlled treadmill exercise was implemented and withdrawn to identify cellular mechanisms associated with exercise capacity and maximal oxygen uptake (&OV0312;2max). Methods and Results—Time-dependent associations between cardiomyocyte dimensions, contractile capacity, and &OV0312;2max were assessed in adult rats after high-level intensity-controlled treadmill running for 2, 4, 8, and 13 weeks and detraining for 2 and 4 weeks. With training, cardiomyocyte length, relaxation, shortening, Ca2+ decay, and estimated cell volume correlated with increased &OV0312;2max (r =0.92, −0.92, 0.88, −0.84, 0.73; P <0.01). Multiple regression analysis identified cell length, relaxation, and Ca2+ decay as the main explanatory variables for V O2max (R2 =0.87, P <0.02). When training stopped, exercise-gained &OV0312;2max decreased 50% within 2 weeks and stabilized at 5% above sedentary controls after 4 weeks. Cardiomyocyte size regressed in parallel with &OV0312;2max and remained (9%) above sedentary after 4 weeks, whereas cardiomyocyte shortening, contraction/relaxation- and Ca2+ ransient time courses, and endothelium-dependent vasorelaxation regressed completely within 2 to 4 weeks of detraining. Cardiomyocyte length, estimated cell volume, width, shortening, and Ca2+decay and endothelium-dependent arterial relaxation all correlated with &OV0312;2max (r =.85, 0.84, 0.75, 0.63, −0.54, −0.37; P <0.01). Multiple regression identified cardiomyocyte length and vasorelaxation as the main determinants for regressed &OV0312;2max during detraining (R2 =0.76, P =0.02). Conclusions—Cardiovascular adaptation to regular exercise is highly dynamic. On detraining, most of the exercise-gained aerobic fitness acquired over 2 to 3 months is lost within 2 to 4 weeks. The close association between cardiomyocyte dimensions, contractile capacity, arterial relaxation, and aerobic fitness suggests cellular mechanisms underlying these changes.

Running speed and maximal oxygen uptake in rats and mice: practical implications for exercise training.

Valid and reliable experimental models are essential to gain insight into the cellular and molecular mechanisms underlying the beneficial effects of exercise in prevention, treatment, and rehabilitation of lifestyle-related diseases. Studies with large changes, low variation, and reproducible training outcome require individualized training intensity, controlled by direct measurements of maximal oxygen uptake or heart rate. As this approach is expensive and time consuming, we discuss whether maximal treadmill running speed in a gradually increasing ramp protocol might be sufficient to control intensity without lossing accuracy. Combined data from six studies of rats and mice from our lab demonstrated a close correlation between running speed and oxygen uptake. This relationship changed towards a steeper linear slope after endurance training, indicating improved work economy, that is, less oxygen was consumed at fixed submaximal running speeds. Maximal oxygen uptake increased 40-70% after high-intensity aerobic interval training in mice and rats. The speed at which oxygen uptake reached a plateau, increased in parallel with the change in maximal oxygen uptake during the training period. Although this suggests that running speed can be used to assess training intensity throughout a training program, the problem is to determine the exact relative intensity related to maximal oxygen uptake from running speed alone. We therefore suggest that directly measured oxygen uptake should be used to assess exercise intensity and optimize endurance training in rats and mice. Running speed may serve as a supplement to ensure this intensity. Eur J Cardiovasc Prev Rehabil 14: 753-760

Intrinsic Aerobic Capacity Sets a Divide for Aging and Longevity

Rationale: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. Objectives: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). Methods and Results: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO2max), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO2max, measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca2+ handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (VO2), and lean body mass were all better sustained with age in rats bred for high aerobic capacity. Conclusions: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.