Electrical pulse stimulation-induced muscle contraction alters the microRNA and mRNA profiles of circulating extracellular vesicles in mice.

Extracellular vesicles, such as exosomes, are secreted by skeletal muscle tissues and may play a role in physiological adaptations induced by exercise. Endurance exercise changes the microRNA (miRNA) profile of circulating extracellular vesicles; however, the effects of resistance exercise are unknown. In this study, we examined the effect of resistance exercise as electrical pulse stimulation (EPS)-induced muscle contraction on the miRNA and mRNA profiles of circulating extracellular vesicles in mice using a comprehensive RNA sequencing-based approach. EPS-induced muscle contraction resulted in changes in the miRNA profile of circulating extracellular vesicles. In particular, 90 min after EPS-induced muscle contraction, a considerable increase in expression of muscle-specific microRNAs, such as miR-1, miR-133, and miR-206, was observed. Furthermore, we found that the expression of 208 mRNAs was considerably altered immediately after EPS-induced muscle contraction and that of 267 mRNAs changed considerably after 90 min. Gene ontology enrichment analysis showed that mRNA expression changes in circulating extracellular vesicles after EPS-induced muscle contraction promoted angiogenesis and regulated the immune response. Changes in the properties of circulating extracellular vesicles owing to muscle contraction may play an important role in resistance exercise-induced physiological adaptations.

Icing after eccentric contraction-induced muscle damage perturbs the disappearance of necrotic muscle fibers and phenotypic dynamics of macrophages in mice.

Icing is still one of the most common treatments to acute skeletal muscle damage in sports medicine. However, previous studies using rodents reported the detrimental effect of icing on muscle regeneration following injury. This study aimed to elucidate the critical factors governing the impairment of muscle regeneration by icing with a murine model of eccentric contraction-induced muscle damage by electrical stimulation. Because of icing after muscle injury, the infiltration of polynuclear and mononuclear cells into necrotic muscle fibers was retarded and attenuated, leading to the persistent presence of necrotic cellular debris. These phenomena coincided with the delayed emergence and sustained accumulation of Pax7+ myogenic cells within the regenerating area. In addition, due to icing, delayed and/or sustained infiltration of M1 macrophages was noted in accordance with the perturbed expression patterns of inflammation-related factors, including tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The key myogenic regulatory factors (i.e., MyoD and myogenin) involved in the activation/proliferation and differentiation of myogenic precursor cells were not altered by icing during the regenerative process. A detailed analysis of regenerating myofibers by size distribution at day 14 after muscle damage showed that the ratio of small regenerating fibers to total regenerating fibers was higher in icing-treated animals than in untreated animals. These findings suggest that icing following muscle damage blunts the efficiency of muscle regeneration by perturbing the removal of necrotic myofibers and phenotypic dynamics of macrophages rather than affecting myogenic factors.NEW & NOTEWORTHY Icing blunted the muscle regeneration by perturbing the infiltration of polynuclear and mononuclear cells into necrotic myofibers and the phenotypic dynamics of macrophages rather than affecting the myogenic regulatory factors. Because of icing, the disappearance of necrotic muscle debris was retarded, coinciding with the delayed emergence and sustained accumulation of Pax7+ cells within the regenerating area. The expression patterns of TNF-α and IL-10 were altered by icing consistent with the perturbation of the macrophage phenotype.

Alterations of macrophage and neutrophil content in skeletal muscle of aged versus young mice.

BACKGROUND: Skeletal muscle inflammation and oxidative stress are associated with aging-related loss of muscle mass and may be attributable to alterations in the number and types of leukocytes in skeletal muscle. Here, we tested the hypothesis that aging changes the number and composition of leukocyte subsets in skeletal muscle tissue. METHODS: Skeletal muscle was sampled from 4-mo-old (young) and 27-mo-old (old) C57BL/6J mice. Mononuclear cells of the gastrocnemius muscle were isolated, and flow cytometry was used to characterize the number and types of immune cells. RESULTS: The number of neutrophils and Ly-6C+ inflammatory macrophages in the skeletal muscle was significantly higher in old mice than in young mice. Inflammation and oxidative stress (measured using the markers phosphorylated JNK and nitrotyrosine) were also higher in the skeletal muscle of old mice than in that of young mice. CONCLUSIONS: Increasing age promotes skeletal muscle inflammation and oxidative stress, as well as infiltration of inflammatory macrophages and neutrophils.

Differential protective effects of Radix astragali, herbal medicine, on immobilization-induced atrophy of slow-twitch and fast-twitch muscles.

Radix astragali is a popular traditional herbal medicine that provides significant protection against tissue injury in various models of oxidative stress-related diseases. In this study, we aimed to investigate whether administration of Radix astragali prevented atrophy in both slow- and fast-twitch muscles following cast immobilization. Twenty-seven 12-week-old male F344 rats were divided into three experimental groups: control (CON), immobilized (IM), and immobilized with Radix astragali administration (IM+AR). Rats in the IM and IM+AR groups were subjected to immobilization of both lower extremities using casting-tape for 14 days. Rats in the IM+AR group were orally administered a decoction of Radix astragali daily for 21 days beginning 7 days before cast immobilization. As expected, rats in the IM group showed significant decreases (P < 0.05) in soleus and plantaris muscle-to-body weight ratios by 74.3% and 70.5%, respectively, compared with those in the CON group. Administration of Radix astragali significantly reversed (+35.5%) the weight reduction observed in soleus muscle, but not in the plantaris muscle, compared with that in the IM group. Furthermore, administration of Radix astragali inhibited MuRF1 mRNA expression only in the soleus muscle during cast immobilization. Our results demonstrated that administration of Radix astragali suppressed the immobilization-induced reductions in skeletal muscle mass and expression of MuRF1 mRNA in slow-twitch soleus muscles, but not in fast-twitch plantaris muscles.

Exercise training suppresses scavenger receptor CD36 expression in kupffer cells of nonalcoholic steatohepatitis model mice.

Although nonalcoholic steatohepatitis (NASH) is an important component of the metabolic syndrome, scavenger receptor CD36 also modulates NASH development. This study aimed to clarify whether exercise training suppresses CD36 expression in a mouse model of NASH. Male C57BL/6 mice were divided into four groups: normal diet (ND) sedentary, ND exercise, high-fat diet and high-fructose water (HFF) sedentary, and HFF exercise groups. The exercise groups were trained on a motorized treadmill at running speeds of 15-20 m/min for 60 min/day, 5 times/week for 16 weeks. CD36 cell surface expression of hepatic resident macrophages, peroxisome proliferator-activated receptor (PPAR)-γ protein, and mRNA levels in the liver were increased in HFF sedentary mice but were attenuated in HFF exercise mice. Hepatic resident macrophages were significantly lower in HFF exercise mice than in HFF sedentary mice. Our findings indicated that exercise training reduced macrophage quantity in the liver, and downregulated CD36 and PPAR-γ expression in liver and macrophages.

Local cyclical compression modulates macrophage function in situ and alleviates immobilization-induced muscle atrophy.

Physical inactivity gives rise to numerous diseases and organismal dysfunctions, particularly those related to aging. Musculoskeletal disorders including muscle atrophy, which can result from a sedentary lifestyle, aggravate locomotive malfunction and evoke a vicious circle leading to severe functional disruptions of vital organs such as the brain and cardiovascular system. Although the significance of physical activity is evident, molecular mechanisms behind its beneficial effects are poorly understood. Here, we show that massage-like mechanical interventions modulate immobilization-induced pro-inflammatory responses of macrophages in situ and alleviate muscle atrophy. Local cyclical compression (LCC) on mouse calves, which generates intramuscular pressure waves with amplitude of 50 mmHg, partially restores the myofiber thickness and contracting forces of calf muscles that are decreased by hindlimb immobilization. LCC tempers the increase in the number of cells expressing pro-inflammatory proteins, tumor necrosis factor-α and monocyte chemoattractant protein-1 (MCP-1), including macrophages in situ The reversing effect of LCC on immobilization-induced thinning of myofibers is almost completely nullified when macrophages recruited from circulating blood are depleted by administration of clodronate liposomes. Furthermore, application of pulsatile fluid shear stress, but not hydrostatic pressure, reduces the expression of MCP-1 in macrophages in vitro Together with the LCC-induced movement of intramuscular interstitial fluid detected by µCT analysis, these results suggest that mechanical modulation of macrophage function is involved in physical inactivity-induced muscle atrophy and inflammation. Our findings uncover the implication of mechanosensory function of macrophages in disuse muscle atrophy, thereby opening a new path to develop a novel therapeutic strategy utilizing mechanical interventions.

Effects of aging on serum levels of lipid molecular species as determined by lipidomics analysis in Japanese men and women.

BACKGROUND: Aging is known to be associated with increased risk of lipid disorders related to the development of type 2 diabetes. Recent evidence revealed that change of lipid molecule species in blood is associated with the risk of type 2 diabetes. However, changes in lipid molecular species induced by aging are still unknown. We assessed the effects of age on the serum levels of lipid molecular species as determined by lipidomics analysis. METHODS: Serum samples were collected from ten elderly men (71.7 ± 0.5 years old) and women (70.2 ± 1.0 years old), ten young men (23.9 ± 0.4 years old), and women (23.9 ± 0.7 years old). Serum levels of lipid molecular species were determined by liquid chromatography mass spectrometry-based lipidomics analysis. RESULTS: Our mass spectrometry analysis revealed increases in the levels of multiple triacylglycerol molecular species in the serum of elderly men and women. Moreover, serum levels of total ester-linked phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased by aging. In contrast, serum levels of specific ether-linked PC and PE molecular species were lower in elderly individuals than in young individuals. CONCLUSIONS: Our finding indicates that specific lipid molecular species, such as ether- and ester- linked phospholipids, may be selectively altered by aging.

Endurance exercise training and high-fat diet differentially affect composition of diacylglycerol molecular species in rat skeletal muscle.

Insulin resistance of peripheral muscle is implicated in the etiology of metabolic syndrome in obesity. Although accumulation of glycerolipids, such as triacylglycerol and diacylglycerol (DAG), in muscle contributes to insulin resistance in obese individuals, endurance-trained athletes also have higher glycerolipid levels but normal insulin sensitivity. We hypothesized that the difference in insulin sensitivity of skeletal muscle between athletes and obese individuals stems from changes in fatty acid composition of accumulated lipids. Here, we evaluated the effects of intense endurance exercise and high-fat diet (HFD) on the accumulation and composition of lipid molecular species in rat skeletal muscle using a lipidomic approach. Sprague-Dawley female rats were randomly assigned to three groups and received either normal diet (ND) in sedentary conditions, ND plus endurance exercise training, or HFD in sedentary conditions. Rats were fed ND or HFD between 4 and 12 wk of age. Rats in the exercise group ran on a treadmill for 120 min/day, 5 days/wk, for 8 wk. Soleus muscle lipidomic profiles were obtained using liquid chromatography/tandem mass spectrometry. Total DAG levels, particularly those of palmitoleate-containing species, were increased in muscle by exercise training. However, whereas the total DAG level in the muscle was also increased by HFD, the levels of DAG molecular species containing palmitoleate were decreased by HFD. The concentration of phosphatidylethanolamine molecular species containing palmitoleate was increased by exercise but decreased by HFD. Our results indicate that although DAG accumulation was similar levels in trained and sedentary obese rats, specific changes in molecular species containing palmitoleate were opposite.

Time-course study of macrophage infiltration and inflammation in cast immobilization-induced atrophied muscle of mice.

INTRODUCTION: Macrophage infiltration may play an important role in mediating the development of muscle atrophy. However, temporal differences in the activation of muscle atrophy signaling pathways and the progress of macrophage infiltration during the atrophic phases of cast immobilization are currently unknown. METHODS: C57BL/6J mice were euthanized after cast immobilization at 1, 3, 7, and 14 days. RESULTS: Skeletal muscle macrophage numbers were unchanged on days 1 and 3 after immobilization, but were elevated on days 7 (2.7-fold, P < 0.01) and 14 (4.1-fold, P < 0.01). Ubiquitin ligase expression was increased 1 and 3 days after cast immobilization, as was the LC3-II/LC3-I ratio. DISCUSSION: Atrophy signaling pathway activation, but not macrophage infiltration, was observed during the early phase after cast immobilization. Our findings indicate that macrophage infiltration may contribute very little to the early phase of muscle atrophy after cast immobilization. Muscle Nerve 57: 1006-1013, 2018.

TLR4-defective (C3H/HeJ) mice are not protected from cast immobilization-induced muscle atrophy.

Recent studies have shown that activation of Toll-like receptor (TLR)4 signaling may be an important factor in muscle atrophy and excessive inflammatory response associated with immobilization. To examine the role of TLR4 signaling on cast immobilization-induced skeletal muscle atrophy, we tested the hypothesis that muscle atrophy and inflammation after cast immobilization is reduced in TLR4-defective mice. TLR4-defective (C3H/HeJ) and wild type (C3H/HeN) mice were divided into control and cast-immobilization groups. Cast immobilization was imposed for 14 days. Cast immobilization increased TLR4 mRNA expression in the gastrocnemius and decreased muscle mass and cross-sectional area (CSA) of the gastrocnemius fibers. However, there was no difference in the gastrocnemius muscle mass and CSA between TLR4-defective and wild type mice. Cast immobilization-induced increase in ubiquitin E3 ligases (MAFbx/Atrogin-1 and MuRF1), inflammatory cytokines, and macrophage/monocyte marker mRNAs were unaffected by defective TLR4. Our findings in C3H/HeJ mice suggested that TLR4 signaling might not play an essential role in immobilization-induced muscle atrophy.

Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase-knockout mice.

Sex steroid hormones, such as estrogen and testosterone, are believed to play important roles in lipid metabolism. To elucidate the effects of estrogen depletion on lipid metabolism in male and female mice, we used aromatase-knockout (ArKO) mice, in which Cyp19 gene disruption prevented estrogen synthesis in vivo. These mice were divided into the following 4 groups: male and female ArKO mice and male and female wild-type (WT) mice. These mice were fed a normal-fat diet (13.6% fat) ad libitum. At 159 days after birth, the mice were tested for liver and plasma lipid content and hepatic hormone receptor- and lipid/lipoprotein metabolism-related gene expression. Interestingly, we found that hepatic steatosis was accompanied by markedly elevated plasma testosterone levels in male ArKO mice but not in female ArKO mice. Plasma lipoprotein profiles exhibited concurrent decreases in LDL- and small dense LDL-triglyceride (TG) levels in male ArKO mice. Moreover, male mice, but not female mice, exhibited marked elevations in androgen receptor (AR), sterol regulatory element-binding protein 1 (SREBP1), and CD36 expression. These results strongly suggest that Cyp19 gene disruption, which induces a sexually dimorphic response and high plasma testosterone levels in male mice, also induces hepatic steatosis.

Neutrophil Depletion Attenuates Muscle Injury after Exhaustive Exercise.

PURPOSE: The infiltration of macrophages in skeletal muscle during exhaustive exercise promotes inflammation, myofiber lesion, and muscle injury. Although neutrophils upregulate macrophage infiltration in skeletal muscles during exercise, the role of neutrophils in promoting muscle injury after exhaustive exercise remains unclear. In this study, we investigated the effects of preexercise neutrophil depletion with antineutrophil antibody treatment on muscle injury, inflammation, and macrophage infiltration after exhaustive exercise. METHODS: Male C57BL/6J mice were randomly assigned to four groups, namely, sedentary with control antibody (n = 10), sedentary with antineutrophil antibody (n = 10), exhaustive exercise with control antibody (n = 10), and exhaustive exercise with antineutrophil antibody (n = 10). The mice were given intraperitoneal injection of the antineutrophil antibody (anti-Ly-6G, clone 1A8) or the control antibody (anti-Ly-6G, clone 2A3), and remained inactive or performed exhaustive exercise on a treadmill 48 h after the injection. Twenty-four hours after the exhaustive exercise, the gastrocnemius muscles were removed for histological and polymerase chain reaction (PCR) analyses. Infiltration of neutrophils and macrophages was evaluated with Ly-6G and F4/80 immunohistochemistry staining procedures. Muscle fiber injury was detected based on the number of IgG staining fiber. The mRNA expression levels of proinflammatory cytokines and chemokines were evaluated with real-time reverse transcription PCR. RESULTS: Exhaustive exercise increased neutrophil infiltration into the gastrocnemius muscle substantially by 3.1-fold and caused muscle injury, but these effects were markedly suppressed by preexercise treatment with antineutrophil antibody (neutrophil infiltration, 0.42-fold, and muscle injury, 0.18-fold). Treatment with antineutrophil antibody also decreased macrophage infiltration (0.44-fold) and mRNA expression of tumor necrosis factor-α (0.55-fold) and interleukin-6 (0.51-fold) in the skeletal muscle after exhaustive exercise. CONCLUSION: These results suggest that neutrophils contribute to exacerbating muscle injury by regulating inflammation through the induction of macrophage infiltration.

Macrophage depletion by clodronate liposome attenuates muscle injury and inflammation following exhaustive exercise.

Exhaustive exercise promotes muscle injury, including myofiber lesions; however, its exact mechanism has not yet been elucidated. In this study, we tested the hypothesis that macrophage depletion by pretreatment with clodronate liposomes alters muscle injury and inflammation following exhaustive exercise. Male C57BL/6J mice were divided into four groups: rest plus control liposome (n=8), rest plus clodronate liposome (n=8), exhaustive exercise plus control liposome (n=8), and exhaustive exercise plus clodronate liposome (n=8). Mice were treated with clodronate liposome or control liposome for 48 h before undergoing exhaustive exercise on a treadmill. Twenty-four hours after exhaustive exercise, the gastrocnemius muscles were removed for histological and PCR analyses. Exhaustive exercise increased the number of macrophages in the muscle; however, clodronate liposome treatment reduced this infiltration. Although exhaustive exercise resulted in an increase in injured myofibers, clodronate liposome treatment following exhaustive exercise reduced the injured myofibers. Clodronate liposome treatment also decreased the mRNA expression levels of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in the skeletal muscle after exhaustive exercise. These results suggest that macrophages play a critical role in increasing muscle injury by regulating inflammation.

Exercise training attenuates neutrophil infiltration and elastase expression in adipose tissue of high-fat-diet-induced obese mice.

The innate immune system is associated with the development of local inflammation. Neutrophils play an essential role in the development of the adipose tissue (AT) inflammation associated with obesity by producing elastase, which can promote the activation and infiltration of macrophages. Exercise training attenuates AT inflammation via suppression of macrophage infiltration. However, the mechanisms driving this phenomenon remains to be elucidated. Here, we evaluated the effects of exercise training on the infiltration of neutrophils and elastase expression in an obese mouse model. Four-week-old male C57BL/6J mice were randomly assigned to one of three groups that either received a normal diet (ND) plus sedentary activity (n = 15), a high-fat diet (HFD) plus sedentary activity (n = 15), or a HFD plus exercise training (n = 15). Mice were fed the ND or HFD from the age of 4 weeks until 20 weeks. Mice in the exercise group ran on a treadmill for 60 min/day, 5 days/week over the same experimental period. Mice fed with the HFD had increased content of macrophages in the AT and increased inflammatory cytokine mRNA levels, which were reduced by exercise training. Similarly, AT from the HFD sedentary mice contained more neutrophils than AT from the ND mice, and the amount of neutrophils in this tissue in HFD-fed mice was lowered by exercise training. The mRNA levels of neutrophil elastase in AT were lower in the HFD exercise-trained mice than those in the HFD sedentary mice. These results suggest that exercise training plays a critical role in reducing macrophage infiltration and AT inflammation by regulating the infiltration of neutrophils.

Low-volume walking program improves cardiovascular-related health in older adults.

Although numerous sources of evidence show that regular physical activity is beneficial to health, most individuals do not engage in a sufficient amount of physical activity to meet the guidelines set out by expert panels. In addition, the minimum amount of physical activity associated with reduced cardiovascular disease risk markers is not clear in older adults. The purpose of this study was to determine the effects of a 12-week walking program involving an exercise volume below the current minimum physical activity recommendation on cardiovascular disease risk markers in older adults. The participants were recruited from the following two groups separately: a walking group (n = 14) and a control group (n = 14). In the walking group, participants walked 30 to 60 minutes per session on 2 days per week for 12 weeks (average walking time, 49.4 ± 8.8 min/session). Plasma oxidised low-density lipoprotein concentrations tended to be lower than baseline values in the walking group after 12 weeks (paired t-test, p = 0.127). The ratio of oxidised low-density lipoprotein to high-density lipoprotein cholesterol was significantly lower than the baseline ratio in the walking group after 12 weeks (paired t-test, p = 0.035). Resting systolic blood pressure and diastolic blood pressure were significantly lower than baseline values in the walking group after 12 weeks (paired t-tests, p = 0.002, p < 0.0005, respectively). Our findings demonstrate that a 12-week walking program comprising a low volume of physical activity confers a benefit to cardiovascular-related health in older adults. Key PointsIt is important to consider baseline physical activity levels when evaluating physical activity program.Being physically active is important to reduce the potential risk marker of cardiovascular disease in older adults.These data imply that a small volume of 12-week walking program confers a benefit to cardiovascular-related health in older adults.

Exhaustive exercise increases the TNF-α production in response to flagellin via the upregulation of toll-like receptor 5 in the large intestine in mice.

Although intense exercise may induce temporary immune depression, it is unclear whether exercise stimulates tumor necrosis factor-alpha (TNF-α) production in response to flagella protein flagellin (FG), which binds to toll-like receptor 5 (TLR5) and induces the production of pro-inflammatory cytokines. Male C3H/HeN mice were administered FG (1mg/kg, i.v.) after exhaustive exercise (EX), and the plasma TNF-α concentrations were examined. The production of TNF-α and the TLR5 expression in both RAW264 and Caco2 cells were measured under FG conditions in vitro. Although the plasma TNF-α concentrations were observed to significantly increase in both the EX and non-EX (N-EX) mice (p<0.01, respectively) following FG injection, the TNF-α levels in the EX mice were significantly higher than those observed in the N-EX mice (p<0.01). Epinephrine (Ep) treatment accelerated the FG-induced TNF-α production and TLR5 expression on the Caco2, but not RAW264 cells. Interestingly, a high Ep-induced TLR5 expression was observed on the Caco2 cell surface, which was inhibited by an inhibitor of phosphoinositide3-kinase (PI3K), Ly294002, as well as a ß-adrenergic blocker, propranolol. In addition, the EX-induced TNF-α production observed in response to FG was also attenuated by pretreatment with propranolol. Our findings suggest that exhaustive exercise upregulates the production of TNF-α in response to FG via a high expression of TLR5 on the intestinal cell surface following the stimulation of ß-adrenergic receptors with exercise.

Curcumin attenuates oxidative stress following downhill running-induced muscle damage.

Downhill running causes muscle damage, and induces oxidative stress and inflammatory reaction. Recently, it is shown that curcumin possesses anti-oxidant and anti-inflammatory potentials. Interestingly, curcumin reduces inflammatory cytokine concentrations in skeletal muscle after downhill running of mice. However, it is not known whether curcumin affects oxidative stress after downhill running-induced muscle damage. Therefore, the purpose of this study was to investigate the effects of curcumin on oxidative stress following downhill running induced-muscle damage. We also investigated whether curcumin affects macrophage infiltration via chemokines such as MCP-1 and CXCL14. Male C57BL/6 mice were divided into four groups; rest, rest plus curcumin, downhill running, or downhill running plus curcumin. Downhill running mice ran at 22 m/min, -15% grade on the treadmill for 150 min. Curcumin (3mg) was administered in oral administration immediately after downhill running. Hydrogen peroxide concentration and NADPH-oxidase mRNA expression in the downhill running mice were significantly higher than those in the rest mice, but these variables were significantly attenuated by curcumin administration in downhill running mice. In addition, mRNA expression levels of MCP-1, CXCL14 and F4/80 reflecting presence of macrophages in the downhill running mice were significantly higher than those in the rest mice. However, MCP-1 and F4/80 mRNA expression levels were significantly attenuated by curcumin administration in downhill running mice. Curcumin may attenuate oxidative stress following downhill running-induced muscle damage.

Exercise training attenuates adipose tissue fibrosis in diet-induced obese mice.

Tissue fibrosis, such as that which occurs in obesity, is associated with chronic inflammatory diseases. Although regular exercise reduces adipose tissue inflammation, the mechanisms regulating the effects of exercise on adipose tissue fibrosis are unclear. This study aimed to clarify whether exercise training attenuates adipose tissue fibrosis with consequent reduction of extracellular matrix including collagens. Male C57BL/6J (4-week old) mice were randomly assigned to four groups that received a normal diet (ND) plus sedentary (n=8), an ND plus exercise training (n=8), a high-fat diet (HFD) plus sedentary (n=12), and an HFD plus exercise training (n=12). Mice were fed the ND or HFD from 4 to 20 weeks of age. The exercise groups were trained on a motorized treadmill for 60 min/day, 5 times/week over the same period. Histological hepatic fibrosis detected by Sirius red and α-smooth muscle actin staining were attenuated in HFD exercise mice compared with HFD sedentary mice. mRNA levels of transforming growth factor-ß and tissue inhibitors of metalloproteinase-1, major regulators of tissue fibrosis, were increased in HFD sedentary mice but were attenuated in HFD exercise mice. Similarly, adipose tissue from the HFD sedentary mice contained higher macrophages than adipose tissue from the ND mice, and this was also lowered by exercise training. These findings suggest that exercise training may be effective for attenuating adipose tissue inflammation in obesity.

Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice.

PURPOSE: Obesity is associated with adipose tissue inflammation, which has been attributed to changes in the number and types of leukocytes in adipose tissue. Exercise training is thought to be important for the reduction of adipose tissue inflammation, but the mechanisms by which this may occur are incompletely understood. Here, we evaluated the effect of exercise training on several inflammation-associated changes in adipose tissue, including infiltration of inflammatory macrophages and T cells. METHODS: Four-week-old male C57BL/6J mice were randomly assigned to four groups that received a normal diet (ND) plus sedentary (n = 8), an ND plus exercise training (n = 8), a high-fat diet (HFD) plus sedentary (n = 12), and an HFD plus exercise training (n = 12). Mice were fed the ND or the HFD from 4 to 20 wk of age. Mice in the exercise groups ran on a treadmill for 60 min·d, 5 d·wk over the same points. RESULTS: Mice fed the HFD had increased numbers of macrophage clusters in adipose tissue, which were reduced by exercise training. Similarly, adipose tissue from the HFD sedentary mice contained higher levels of tumor necrosis factor α mRNA and increased numbers of CD11c inflammatory macrophages and CD8 T cells than adipose tissue from the ND mice, and those were also lowered by exercise training. The mRNA levels of monocyte chemoattractant proteins 1 and 2 and macrophage inflammatory proteins 1α and 1ß in adipose tissue were lower in the HFD exercise mice than those in the HFD sedentary mice. CONCLUSIONS: The results suggest that exercise training reduces adipose tissue inflammation by suppressing infiltration of inflammatory macrophages and CD8 T cells.

Effects of low-volume walking programme and vitamin E supplementation on oxidative damage and health-related variables in healthy older adults.

BACKGROUND: Both exercise and vitamin E supplementation have been shown to reduce oxidative stress and cardiovascular disease risk in older adults, and when combined there is evidence suggesting that they act synergistically. The currently recommended amount of exercise for older adults is 150 min/week of moderate-intensity exercise; however, the minimum amount of exercise necessary to achieve health benefits is not known. The purpose of this study was to investigate the effects of 12 weeks of participation in a low-volume walking exercise programme (i.e. 90 min/week) combined with daily vitamin E supplementation on thiobarbituric acid reactive substances (TBARS) and oxidised low-density lipoprotein (LDL) concentrations in older adults. METHODS: The participants were recruited from the following four groups separately: 1) control (CG, n = 14), 2) vitamin E supplementation (SG, n = 10), 3) walking (WG, n = 7), or 4) walking + supplementation (WSG, n = 7). In the CG, participants were advised to maintain their normal lifestyle during the study. Participants in both the SG and WSG received 450 IU (300 mg) /day of α-tocopherol for 12 weeks. The exercise programme for the WG and WSG consisted of two 30-60 minute sessions weekly for 12 weeks (average walking time was 44.5 ± 1.6 min/session). Blood samples were collected at baseline and at 12 weeks. RESULTS: Delta plasma oxidised LDL concentrations did not differ among four groups (One-factor ANOVA, P = 0.116). However, negative delta plasma TBARS, a marker of oxidative damage, concentrations were observed in the WG, WSG and SG relative to the CG at the end of the study period (One-factor ANOVA, P = 0.001; post hoc tests; CG compared with WG, WSG and SG, P = 0.005; P = 0.021; P = 0.024, respectively). CONCLUSION: These findings suggest that a low-volume of physical activity and/or vitamin E supplementation may be an effective intervention strategy for reducing TBARS concentrations of older adults. TRIAL REGISTRATION: UMIN000008304.