Ilkka Heinonen

Long-term Leisure-time Physical Activity and Serum Metabolome

Background— Long-term physical inactivity seems to cause many health problems. We studied whether persistent physical activity compared with inactivity has a global effect on serum metabolome toward reduced cardiometabolic disease risk. Methods and Results— Sixteen same-sex twin pairs (mean age, 60 years) were selected from a cohort of twin pairs on the basis of their >30-year discordance for physical activity. Persistently (≥5 years) active and inactive groups in 3 population-based cohorts (mean ages, 31–52 years) were also studied (1037 age- and sex-matched pairs). Serum metabolome was quantified by nuclear magnetic resonance spectroscopy. We used permutation analysis to estimate the significance of the multivariate effect combined across all metabolic measures; univariate effects were estimated by paired testing in twins and in matched pairs in the cohorts, and by meta-analysis over all substudies. Persistent physical activity was associated with the multivariate metabolic profile in the twins (P=0.003), and a similar pattern was observed in all 3 population cohorts with differing mean ages. Isoleucine, &agr;1-acid glycoprotein, and glucose were lower in the physically active than in the inactive individuals (P<0.001 in meta-analysis); serum fatty acid composition was shifted toward a less saturated profile; and lipoprotein subclasses were shifted toward lower very-low-density lipoprotein (P<0.001) and higher large and very large high-density lipoprotein (P<0.001) particle concentrations. The findings persisted after adjustment for body mass index. Conclusions— The numerous differences found between persistently physically active and inactive individuals in the circulating metabolome together indicate better metabolic health in the physically active than in inactive individuals.

Local heating, but not indirect whole body heating, increases human skeletal muscle blood flow.

For decades it was believed that direct and indirect heating (the latter of which elevates blood and core temperatures without directly heating the area being evaluated) increases skin but not skeletal muscle blood flow. Recent results, however, suggest that passive heating of the leg may increase muscle blood flow. Using the technique of positron-emission tomography, the present study tested the hypothesis that both direct and indirect heating increases muscle blood flow. Calf muscle and skin blood flows were evaluated from eight subjects during normothermic baseline, during local heating of the right calf [only the right calf was exposed to the heating source (water-perfused suit)], and during indirect whole body heat stress in which the left calf was not exposed to the heating source. Local heating increased intramuscular temperature of the right calf from 33.4 ± 1.0°C to 37.4 ± 0.8°C, without changing intestinal temperature. This stimulus increased muscle blood flow from 1.4 ± 0.5 to 2.3 ± 1.2 ml·100 g⁻¹·min⁻¹ (P < 0.05), whereas skin blood flow under the heating source increased from 0.7 ± 0.3 to 5.5 ± 1.5 ml·100 g⁻¹·min⁻¹ (P < 0.01). While whole body heat stress increased intestinal temperature by ∼1°C, muscle blood flow in the calf that was not directly exposed to the water-perfused suit (i.e., indirect heating) did not increase during the whole body heat stress (normothermia: 1.6 ± 0.5 ml·100 g⁻¹·min⁻¹; heat stress: 1.7 ± 0.3 ml·100 g⁻¹·min⁻¹; P = 0.87). Whole body heating, however, reflexively increased calf skin blood flow (to 4.0 ± 1.5 ml·100 g⁻¹·min⁻¹) in the area not exposed to the water-perfused suit. These data show that local, but not indirect, heating increases calf skeletal muscle blood flow in humans. These results have important implications toward the reconsideration of previously accepted blood flow distribution during whole body heat stress.

Sedentary behaviours and obesity in adults: the Cardiovascular Risk in Young Finns Study

Objective Sedentary behaviour may contribute to the development of obesity. We investigated the relations between different types of sedentary behaviour and adiposity markers in a well-characterised adult population after controlling for a wide range of potential confounders. Design Cross-sectional study. Setting The Cardiovascular Risk in Young Finns Multicenter Study. Participants Sedentary time (TV viewing, computer time, reading, music/radio listening and other relaxation) was assessed with a questionnaire for 1084 women and 909 men aged 30–45u2005years. Other study variables included occupational and leisure-time physical activity, sleep duration, socioeconomic status, smoking, alcohol consumption, energy intake, adherence to the recommended diet, multiple individual food items, age and genetic variants associated with body mass index (BMI). Primary outcome measures BMI in kg/m2 and waist circumference (WC in cm). Results Of the different sedentary behaviour types, TV viewing was most consistently related to higher BMI and WC, both in men and women. One additional daily TV hour was associated with a 1.81±0.44u2005cm larger WC in women and 2u2005cm±0.44u2005cm in men (both p<0.0001). The association with TV was diluted, but remained highly significant after adjustments with all measured covariates, including several potentially obesogenic food items associated with TV viewing. The intakes of food items such as sausage, beer and soft drinks were directly associated with TV viewing, while the intakes of oat and barley, fish, and fruits and berries were associated indirectly. After these adjustments, non-TV sedentary behaviour remained associated with adiposity indices only in women. Conclusions Out of the different types of sedentary behaviour, TV viewing was most consistently associated with adiposity markers in adults. Partial dilution of these associations after adjustments for covariates suggests that the obesogenic effects of TV viewing are partly mediated by other lifestyle factors.

The effects of equal caloric high fat and western diet on metabolic syndrome, oxidative stress and vascular endothelial function in mice

Nutrition contributes to increased adiposity, but it remains to be determined whether high fat rather than Western diet exacerbates the development of obesity and other characteristics of metabolic syndrome and vascular function.

Increasing exercise intensity reduces heterogeneity of glucose uptake in human skeletal muscles.

Proper muscle activation is a key feature of survival in different tasks in daily life as well as sports performance, but can be impaired in elderly and in diseases. Therefore it is also clinically important to better understand the phenomenon that can be elucidated in humans non-invasively by positron emission tomography (PET) with measurements of spatial heterogeneity of glucose uptake within and among muscles during exercise. We studied six healthy young men during 35 minutes of cycling at relative intensities of 30% (low), 55% (moderate), and 75% (high) of maximal oxygen consumption on three separate days. Glucose uptake in the quadriceps femoris muscle group (QF), the main force producing muscle group in recreational cycling, and its four individual muscles, was directly measured using PET and 18F-fluoro-deoxy-glucose. Within-muscle heterogeneity was determined by calculating the coefficient of variance (CV) of glucose uptake in PET image voxels within the muscle of interest, and among-muscles heterogeneity of glucose uptake in QF was expressed as CV of the mean glucose uptake values of its separate muscles. With increasing intensity, within-muscle heterogeneity decreased in the entire QF as well as within its all four individual parts. Among-muscles glucose uptake heterogeneity also decreased with increasing intensity. However, mean glucose uptake was consistently lower and heterogeneity higher in rectus femoris muscle that is known to consist of the highest percentage of fast twitch type II fibers, compared to the other three QF muscles. In conclusion, these results show that in addition to increased contribution of distinct muscle parts, with increases in exercise intensity there is also an enhanced recruitment of muscle fibers within all of the four heads of QF, despite established differences in muscle-part specific fiber type distributions. Glucose uptake heterogeneity may serve as a useful non-invasive tool to elucidate muscle activation in aging and diseased populations.

The microcirculation: a key player in obesity-associated cardiovascular disease

It is increasingly recognized that obesity is a risk factor for microvascular disease, involving both structural and functional changes in the microvasculature. This review aims to describe how obesity impacts the microvasculature of a variety of tissues, including visceral adipose tissue, skeletal muscle, heart, brain, kidneys, and lungs. These changes involve endothelial dysfunction, which in turn (i) impacts control of vascular tone, (ii) contributes to development of microvascular insulin resistance, (iii) alters secretion of paracrine factors like nitric oxide and endothelin, but (iv) also influences vascular structure and perivascular inflammation. In concert, these changes impair organ perfusion and organ function thereby contributing to altered release and clearance of neurohumoral factors, such as adipokines and inflammatory cytokines. Global microvascular dysfunction in obese subjects is therefore a common pathway that not only explains exercise-intolerance but also predisposes to development of chronic kidney disease, microvascular dementia, coronary microvascular angina, heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, and pulmonary hypertension.

Muscle-specific glucose and free fatty acid uptake after sprint interval and moderate-intensity training in healthy middle-aged men

We tested the hypothesis that sprint interval training (SIT) causes larger improvements in glucose and free fatty acid uptake (FFAU) in lower and upper body muscles than moderate-intensity training (MIT). Twenty-eight healthy, untrained, middle-aged men were randomized into SIT (n = 14, 4-6 × 30 s of all-out cycling/4 min recovery) and MIT groups [n = 14, 40-60 min cycling at 60% of peak O2 uptake (V̇o2 peak)] and completed six training sessions within 2 wk. Pre- and postmeasurements included V̇o2 peak, whole body (M-value), muscle-specific insulin-stimulated glucose uptake (GU), and fasting FFAU measured with positron emission tomography in thigh [quadriceps femoris (QF) and hamstrings] and upper body (deltoids, biceps, and triceps brachii) muscles. V̇o2 peak and M-value improved significantly by 6 and 12% in SIT, and 3 and 8% in MIT, respectively,. GU increased significantly only in the QF, and there was no statistically significant difference between the training modes. GU increased in all four heads of QF in response to SIT, but only in the vasti muscles in response to MIT, whereas in rectus femoris the response was completely lacking. Training response in FFAU in QF was smaller and nonsignificant, but it also differed between the training modes in the rectus femoris. In conclusion, SIT and MIT increased insulin-stimulated GU only in the main working muscle QF and not in the upper body muscles. In addition, the biarticular rectus femoris did not respond to moderate-intensity training, reflecting most probably poor activation of it during moderate-intensity cycling.

Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart

Highly endurance-trained athlete’s heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [15O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70xa0±xa021 vs. 63xa0±xa011xa0% at rest and 86xa0±xa013 vs. 73xa0±xa010xa0% during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (pxa0=xa00.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.

α-Melanocyte-stimulating hormone regulates vascular NO availability and protects against endothelial dysfunction

AIMSnα-Melanocyte-stimulating hormone (α-MSH), derived from the precursor molecule pro-opiomelanocortin, exerts potent anti-inflammatory actions in the vasculature, but its role in circulatory regulation remains unclear. Therefore, we sought to investigate whether α-MSH could regulate the local control of blood vessel tone.nnnMETHODS AND RESULTSnUsing in vivo and ex vivo methods to assess vascular reactivity, we found that α-MSH improved endothelium-dependent vasodilatation in the mouse aorta and coronary circulation without directly contracting or relaxing blood vessels. α-MSH promoted vasodilatation by enhancing endothelial nitric oxide (NO) formation and by improving sensitivity to endothelium-independent blood vessel relaxation. Using cultured human endothelial cells to elucidate the involved molecular mechanisms, we show that α-MSH increased the expression and phosphorylation of endothelial NO synthase in these cells. The observed effects were regulated by melanocortin 1 (MC1) receptors expressed in the endothelium. In keeping with the vascular protective role of α-MSH, in vivo treatment with stable analogues of α-MSH ameliorated endothelial dysfunction associated with aging and diet-induced obesity in mice.nnnCONCLUSIONnThe present study identifies α-MSH and endothelial MC1 receptors as a new signalling pathway contributing to the regulation of NO availability and vascular function. These findings suggest applicability of α-MSH analogues for therapeutic use in pathological conditions that are characterized by vascular dysfunction.

Effect of nitric oxide synthase inhibition on the exchange of glucose and fatty acids in human skeletal muscle

BackgroundThe role of nitric oxide in controlling substrate metabolism in humans is incompletely understood.MethodsThe present study examined the effect of nitric oxide blockade on glucose uptake, and free fatty acid and lactate exchange in skeletal muscle of eight healthy young males. Exchange was determined by measurements of muscle perfusion by positron emission tomography and analysis of arterial and femoral venous plasma concentrations of glucose, fatty acids and lactate. The measurements were performed at rest and during exercise without (control) and with blockade of nitric oxide synthase (NOS) with NG-monomethyl-l-arginine (L-NMMA).ResultsGlucose uptake at rest was 0.40u2009±u20090.21 μmol/100 g/min and increased to 3.71u2009±u20092.53 μmol/100 g/min by acute one leg low intensity exercise (pu2009<u20090.01). Prior inhibition of NOS by L-NMMA did not affect glucose uptake, at rest or during exercise (0.40u2009±u20090.26 and 4.74u2009±u20092.69 μmol/100 g/min, respectively). In the control trial, there was a small release of free fatty acids from the limb at rest (−0.05u2009±u20090.09 μmol/100 g/min), whereas during inhibition of NOS, there was a small uptake of fatty acids (0.04u2009±u20090.05 μmol/100 g/min, pu2009<u20090.05). During exercise fatty acid uptake was increased to (0.89u2009±u20091.07 μmol/100 g/min), and there was a non-significant trend (pu2009=u20090.10) for an increased FFA uptake with NOS inhibition 1.23u2009±u20091.48 μmol/100 g/min) compared to the control condition. Arterial concentrations of all substrates and exchange of lactate over the limb at rest and during exercise remained unaltered during the two conditions.ConclusionIn conclusion, inhibition of nitric oxide synthesis does not alter muscle glucose uptake during low intensity exercise, but affects free fatty acid exchange especially at rest, and may thus be involved in the modulation of energy metabolism in the human skeletal muscle.