Shumpei Fujie

Endurance Training-Induced Increase in Circulating Irisin Levels Is Associated with Reduction of Abdominal Visceral Fat in Middle-Aged and Older Adults

To elucidate the effects of endurance training on circulating irisin levels in young and middle-aged/older adults, and to determine the association between endurance training-induced alteration of irisin and reduction in body fat. Twenty-five healthy young (age 21 ± 1 years; 16 men, 9 women) and 28 healthy middle-aged/older adults (age 67 ± 8 years; 12 men, 16 women) participated in the study. Each age cohort was divided into two groups: the endurance-training group (14 young, 14 middle-aged/older) and the control group. Subjects in the training groups completed an 8-week endurance-training program (cycling at 60-70% peak oxygen uptake [V˙O2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated serum irisin level, V˙O2peak, and body composition. The increase in V˙O2peak in the young and middle-aged/older training groups after the intervention period was significantly greater than those in the young and middle-aged/older control groups (P < 0.05). Serum irisin level was significantly increased in the middle-aged/older training group after the intervention period (P < 0.01), but not in the young training group. Furthermore, in the middle-aged/older training group, the endurance training-induced reduction in visceral adipose tissue area was negatively correlated with the change in serum irisin level (r = −0.54, P < 0.05). These results suggest a possible role for secreted irisin in the exercise-induced alteration of abdominal visceral fat in middle-aged and older adults.

Reduction of arterial stiffness by exercise training is associated with increasing plasma apelin level in middle-aged and older adults.

Aging-induced deterioration of arterial stiffness is decreased by regular exercise, and increased nitric oxide (NO) production participates in this effect. Apelin regulates endothelial NO synthase in endothelial cells, promoting NO production. However, the effect of aerobic exercise training on circulating apelin levels in healthy middle-aged and older adults remains unknown. Accordingly, this study aimed to clarify the effects of regular aerobic exercise on apelin concentrations in middle-aged and older adults. Thirty-four healthy middle-aged and older subjects (67.0 ± 1.3 years) were randomly divided into two groups: exercise intervention and sedentary controls. Subjects in the training group completed 8-week of aerobic exercise training (60–70% peak oxygen uptake [VO2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated plasma apelin and nitrite/nitrate (NOx) concentrations, VO2peak, and arterial stiffness index. In the training group, VO2peak was significantly increased, and carotid β-stiffness was significantly decreased, after the intervention (P<0.05). Moreover, plasma apelin and NOx levels were significantly increased in the training group after the intervention (P<0.05). Additionally, there was a correlation between the training effects of plasma apelin levels and carotidβ-stiffness (r = −0.508, P = 0.032) and plasma NOx levels (r = 0.494, P = 0.037). By contrast, none of these parameters changed significantly in the control group. These results suggest that the increased in plasma apelin levels may be associated with exercise training-induced alternation of arterial stiffness in middle-aged and older adults.

Aerobic exercise training-induced changes in serum adropin level are associated with reduced arterial stiffness in middle-aged and older adults

Aging-induced arterial stiffening is reduced by aerobic exercise training, and elevated production of nitric oxide (NO) participates in this effect. Adropin is a regulator of endothelial NO synthase and NO release, and circulating adropin level decreases with age. However, the effect of habitual aerobic exercise on circulating adropin levels in healthy middle-aged and older adults remains unclear. We sought to determine whether serum adropin level is associated with exercise training-induced changes in arterial stiffness. First, in a cross-sectional study, we investigated the association between serum adropin level and both arterial stiffness and cardiorespiratory fitness in 80 healthy middle-aged and older subjects (65.6 ± 0.9 yr). Second, in an intervention study, we examined the effects of 8-wk aerobic exercise training on serum adropin level and arterial stiffness in 40 healthy middle-aged and older subjects (67.3 ± 1.0 yr) divided into two groups: aerobic exercise training and sedentary controls. In the cross-sectional study, serum adropin level was negatively correlated with carotid β-stiffness (r = -0.437, P < 0.001) and positively correlated with plasma NOx level (r = 0.493, P < 0.001) and cardiorespiratory fitness (r = 0.457, P < 0.001). Serum adropin levels were elevated after the 8-wk aerobic exercise training intervention, and training-induced changes in serum adropin level were correlated with training-induced changes in carotid β-stiffness (r = -0.399, P < 0.05) and plasma NOx level (r = 0.623, P < 0.001). Thus the increase in adropin may participate in the exercise-induced reduction of arterial stiffness.

Elevated pentraxin 3 level at the early stage of exercise training is associated with reduction of arterial stiffness in middle-aged and older adults

Regular exercise improves aging-induced deterioration of arterial stiffness, and is associated with elevated production of pentraxin 3 (PTX3) and anti-inflammatory as well as anti-atherosclerotic effects. However, the time-dependent effect of exercise training on arterial stiffness and PTX3 production remains unclear. The purpose of this study was to investigate the time course of the association between the effects of training on the circulating PTX3 level and arterial stiffness in middle-aged and older adults. Thirty-two healthy Japanese subjects (66.2±1.3 year) were randomly divided into two groups: training (exercise intervention) and sedentary controls. Subjects in the training group completed 8 weeks of aerobic exercise training (60–70% peak oxygen uptake (VO2peak) for 45 min, 3 days per week); during the training period, we evaluated plasma PTX3 concentration and carotid–femoral pulse wave velocity (cfPWV) every 2 wk. cfPWV gradually declined over the 8-week training period, and was significantly reduced after 6 and 8 week of exercise intervention (P<0.05). Plasma PTX3 level was significantly increased after 4 weeks of the intervention (P<0.05). In addition, the exercise training–induced reduction in cfPWV was negatively correlated with the percent change in plasma PTX3 level after 6 week (r=−0.54, P<0.05) and 8 weeks (r=−0.51, P<0.05) of the intervention, but not correlated at 4 weeks. Plasma PTX3 level was elevated at the early stage of the exercise training intervention, and was subsequently associated with training-induced alteration of arterial stiffness in middle-aged and older adults.

Higher cardiorespiratory fitness attenuates arterial stiffening associated with the Ala54Thr polymorphism in FABP2

Fatty acid binding protein 2 (FABP2) Ala54Thr polymorphism is a candidate gene associated with the risk of cardiovascular disease. Habitual exercise brings higher cardiorespiratory fitness and results in the improvement of cardiovascular disease risk. However, the effect of cardiorespiratory fitness level and FABP2 Ala54Thr polymorphism on the risk of cardiovascular diseases remains unclear. In the present study, a cross-sectional investigation of 837 Japanese men and women was performed to clarify the effects of cardiorespiratory fitness on the relationship between risk of cardiovascular disease and FABP2 Ala54Thr gene polymorphism. The study subjects were divided into high-cardiorespiratory fitness (High-Fit) and low-cardiorespiratory fitness (Low-Fit) groups based on the median value of peak oxygen uptake in each sex and decade. The FABP2 Ala54Thr polymorphism did not significantly affect carotid β-stiffness or blood pressure. In the Low-Fit group, carotid β-stiffness, systolic blood pressure, and diastolic blood pressure were higher for individuals with the Ala/Ala genotype compared with those with the Ala/Thr or Thr/Thr genotype, whereas no differences were observed in the High-Fit group. Additionally, serum triglyceride and plasma glucose levels were lower and serum high-density lipoprotein cholesterol levels were higher in the High-Fit group compared with the Low-Fit group; the FABP2 Ala54Thr polymorphism did not significantly affect these parameters. These results suggest that the higher cardiorespiratory fitness may attenuate the changes in central arterial stiffness and blood pressure that are associated with the FABP2 genotype.

Intramyocellular and Extramyocellular Lipids Are Associated With Arterial Stiffness.

BACKGROUND Obese and overweight patients are at increased risk of arterial stiffness, and visceral, epicardial and hepatic fat accumulation is associated with cardiovascular disease risk. In general, muscular lipids are stored either in interstitial adipose tissue (extramyocellular lipid (EMCL)) or in lipid droplets within muscle cells (intramyocellular lipid (IMCL)). However, the association between IMCL or EMCL content and arterial stiffness remains unclear. This cross-sectional study aimed to clarify this association. METHODS A total of 237 subjects (18-81 years) were enrolled in this study. The IMCL and EMCL contents of the right vastus lateralis muscle were evaluated by proton magnetic resonance spectroscopy. Arterial stiffness was estimated using brachial-ankle pulse wave velocity (baPWV). RESULTS There were significant correlations between baPWV and the contents of both IMCL (R = -0.23, P < 0.001) and EMCL (R = 0.53, P < 0.001) in all subjects. The baPWV negatively correlated with IMCL content (R = -0.45, P < 0.001) in females only. In contrast, significant positive correlations were observed between baPWV and EMCL content in both males (R = 0.59, P < 0.001) and females (R = 0.55, P < 0.001). IMCL and EMCL contents contributed independently to baPWV variation after adjustment for age, sex, body mass index, visceral and subcutaneous abdominal fat, upper and lower limb fat, blood pressure, heart rate, and lipid profiles. CONCLUSION These results suggest that IMCL and EMCL contents may be a risk factor for arterial stiffness, and this association differed with gender and age.

Association between aerobic exercise training effects of serum adropin level, arterial stiffness, and adiposity in obese elderly adults

Serum levels of adropin, which enhances endothelial cell release of nitric oxide (NO), are lower in obese patients. Although habitual aerobic exercise reduces arterial stiffness and adiposity, the relationship between these effects and circulating levels of adropin remains unclear. The purpose of this study was to determine if serum adropin level is associated with the effects of aerobic exercise training on arterial stiffness and adiposity in obese adults. In Experiment 1, we examined whether serum adropin levels are associated with cardiorespiratory fitness, carotid β-stiffness, plasma nitrite/nitrate (NOx) level, and abdominal visceral fat in 27 normal, 20 overweight, and 25 obese adults (age, 41-79 years). In Experiment 2, we examined the effects of an 8-week aerobic exercise training program on the relationship between serum adropin level and arterial stiffness or adiposity in 13 obese adults (age, 54-76 years). Serum adropin levels in normal, overweight, and obese adults negatively correlated with carotid β-stiffness and abdominal visceral fat, and positively correlated with plasma NOx level and cardiorespiratory fitness. After the 8-week exercise program, serum adropin levels in obese adults were elevated, and correlated with training-induced changes in carotid β-stiffness (r = -0.573, P < 0.05), plasma NOx level (r = 0.671, P < 0.05), and abdominal visceral fat (r = -0.585, P < 0.05). These findings suggest that the exercise training-induced increase in serum adropin may be related to the training effects of arterial stiffness and adiposity in obese adults.

Effects of habitual aerobic exercise on the relationship between intramyocellular or extramyocellular lipid content and arterial stiffness.

The accumulation of intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) is associated with arterial stiffness in middle-aged and older adults. Habitual aerobic exercise induces the improvement of arterial stiffness with reduction in fat accumulation. However, the relationship between aerobic exercise-induced changes in muscular lipids and arterial stiffness remains unclear. The purpose of this study was to investigate whether habitual aerobic exercise-induced changes in IMCL and EMCL content would lead to an improvement of arterial stiffness. First, in a cross-sectional study, we investigated whether cardiorespiratory fitness level affects the association between IMCL or EMCL content and arterial stiffness in 60 middle-aged and older subjects (61.0±1.3 years). Second, in an intervention study, we examined whether aerobic exercise training-induced changes in IMCL and EMCL content are associated with a reduction in arterial stiffness in 18 middle-aged and older subjects (67.0±1.7 years). In the cross-sectional study, IMCL content was negatively correlated with brachial-ankle pulse wave velocity (baPWV) (r=−0.47, P<0.05), whereas EMCL content was positively correlated with baPWV (r=0.48, P<0.05) in the low-fitness group, but was not correlated in the high-fitness group. Furthermore, 8-week aerobic exercise training in older adults increased IMCL content and reduced EMCL content. The training-induced change in baPWV was negatively correlated with training-induced changes in IMCL but was positively correlated with training-induced changes in EMCL. These findings suggest that aerobic exercise training-induced changes in IMCL and EMCL content may be related to a reduction in arterial stiffness in middle-aged and older adults.

Resistance training prevents muscle fibrosis and atrophy via down-regulation of C1q-induced Wnt signaling in senescent mice

Increased complement component 1q (C1q) secretion with aging leads to muscle fibrosis and atrophy whereas resistance training attenuates circulating C1q levels. This study aimed to clarify whether resistance exercise‐induced reduction of C1q secretion contributes to the inhibition of fibrosis and atrophy in aged muscles. Young (13‐wk‐old) and aged (38‐wk‐old) senescence‐accelerated mouse prone 1 mice were randomly assigned to one of 4 groups: a young or aged sedentary control group, or a young or aged resistance training (climbing a ladder 3 d/wk for 12 wk) group. We found that resistance training ameliorated muscle fibrosis and atrophy in aged mice, concomitant with decreased circulating and muscle C1q levels and attenuated activation of muscle Wnt signaling (glycogen synthase kinase β/β‐catenin), including β‐catenin in satellite (Pax7+/DAPI+) and fibroblast (vimentin+/DAPI+) cells. Furthermore, during muscle regeneration after mice were injured by cardiotoxin injection, we observed a reduction in circulating C1q levels, the inhibition of muscle fibrosis and repair, and decreased in the activation of muscle cytoplasmic and nuclear β‐catenin in aged mice from the resistance training group, but these effects were cancelled by a single preadministration of exogenous recombinant C1q. In addition, resistance training attenuated aging‐related muscle loss concomitant with decreased expression of both muscle ring‐finger protein 1 and muscle atrophy F‐box in the muscle. Thus, resistance training‐induced changes in circulating C1q levels may contribute to the prevention of muscle fibrosis and atrophy via muscle Wnt signaling in senescent mice.—Horii, N., Uchida, M., Hasegawa, N., Fujie, S., Oyanagi, E., Yano, H., Hashimoto, T., Iemitsu, M. Resistance training prevents muscle fibrosis and atrophy via down‐regulation of C1q‐induced Wnt signaling in senescent mice. FASEB J. 32, 3547–3559 (2018). www.fasebj.org

Aerobic exercise training-induced changes in serum C1q/TNF-related protein levels are associated with reduced arterial stiffness in middle-aged and older adults

Adiponectin regulates endothelial nitric oxide synthase in endothelial cells, and body fat loss by aerobic exercise training promotes adiponectin secretion. Recently, C1q/tumor necrosis factor-related proteins (CTRPs) have been identified as novel adipokines and are paralogs of adiponectin, but the association between exercise training-induced reduction of arterial stiffness and circulating CTRPs levels remains unclear. This study aimed to clarify whether the reduction of arterial stiffness in middle-aged and older adults is associated with the change in serum levels of CTRPs induced by exercise training. A total of 52 middle-aged and older participants were randomly divided into two groups: a training group ( n = 26) and a sedentary control group ( n = 26). Participants in the training group completed 8 wk of aerobic exercise training (60-70% peak oxygen uptake for 45 min, 3 days/wk). The reduction of percent whole body fat, abdominal visceral fat area, and carotid-femoral pulse-wave velocity (cfPWV) was significantly greater in the training group than in the control group ( P < 0.05). Moreover, the increase in serum adiponectin, CTRP3, and CTRP5 from baseline to 8 wk was significantly higher in the training group compared with the control group ( P < 0.05). Additionally, the training-induced change in cfPWV was negatively correlated with the training-induced change in serum adiponectin, CTRP3, and CTRP5 levels ( r = -0.51, r = -0.48, r = -0.42, respectively, P < 0.05), and increased plasma nitrite/nitrate level by exercise training was correlated only with adiponectin levels ( r = 0.41, P < 0.05). These results suggest that the exercise training-induced increase in serum CTRPs levels may be associated with the reduction of arterial stiffness in middle-aged and older adults.