Acute aerobic exercise (AE) increases skeletal muscle insulin sensitivity for several hours, caused by acute activation of AMP-activated protein kinase (AMPK). Acute resistance exercise (RE) also ...activates AMPK, possibly improving insulin-stimulated glucose uptake. However, RE-induced rapamycin-sensitive mechanistic target of rapamycin complex 1 (mTORC1) activation is higher and has a longer duration than after AE. In molecular studies, mTORC1 was shown to be upstream of insulin receptor substrate 1 (IRS-1) Ser phosphorylation residue, inducing insulin resistance. Therefore, we hypothesised that although RE increases insulin sensitivity through AMPK activation, prolonged mTORC1 activation after RE reduces RE-induced insulin sensitising effect. In this study, we used an electrical stimulation-induced RE model in rats, with rapamycin as an inhibitor of mTORC1 activation. Our results showed that RE increased insulin-stimulated glucose uptake following AMPK signal activation. However, mTORC1 activation and IRS-1 Ser632/635 and Ser612 phosphorylation were elevated 6 h after RE, with concomitant impairment of insulin-stimulated Akt signal activation. By contrast, rapamycin inhibited these prior exercise responses. Furthermore, increases in insulin-stimulated skeletal muscle glucose uptake 6 h after RE were higher in rats with rapamycin treatment than with placebo treatment. Our data suggest that mTORC1/IRS-1 signaling inhibition enhances skeletal muscle insulin-sensitising effect of RE.
Resistance exercise training induces skeletal muscle hypertrophy, but repeated bouts gradually attenuate this anabolic effect. Attenuation of mechanistic target of rapamycin complex 1 (mTORC1) ...activation by repetitive resistance exercise is involved in this process, but the mechanism leading to inactivation of mTORC1 remains unclear. In this study, we investigated repetition-dependent changes in mitogen-activated protein kinases (MAPKs) and the 90-kDa ribosomal S6 kinase (p90RSK), upstream regulators of mTORC1, in a rat resistance-exercise model. Resistance exercise was associated with increased phosphorylation of 70-kDa ribosomal protein S6 kinase (Thr389), but its magnitude was decreased with repeated bouts. Additionally, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) and p38 MAPK (Thr180/Tyr182), which are MAPKs, decreased with repeated bouts. A similar result was also observed for p90RSK phosphorylation (Thr573). These observations indicate that repeated bouts desensitized ERK1/2 and p38 MAPK, subsequently attenuating p90RSK phosphorylation. This reduction in p90RSK phosphorylation may have been partly responsible for the blunting of mTORC1 activation by resistance exercise.
•Resistance exercise training gradually attenuates anabolic effect per bouts.•Repeated bouts attenuated response of mTORC1 to same amount of mechanical stress.•Repeated bouts blunted ERK1/2, p38 MAPK, and subsequently p90RSK phosphorylation.•These are partly responsible for blunting mTORC1 activation and muscle hypertrophy.
Skeletal muscle mass is critical for good quality of life. Mesenchymal stem cells (MSCs) are multipotent stem cells distributed across various tissues. They are characterized by the capacity to ...secrete growth factors and differentiate into skeletal muscle cells. These capabilities suggest that MSCs might be beneficial for muscle growth. Nevertheless, little is known regarding the effects on muscle protein anabolic and catabolic systems of intramuscular injection of MSCs into skeletal muscle. Therefore, in the present study, we measured changes in mechanistic target of rapamycin complex 1 (mTORC1) signaling, the ubiquitin-proteasome system, and autophagy-lysosome system-related factors after a single intramuscular injection of MSCs with green fluorescence protein (GFP) into mouse muscles. The intramuscularly-injected MSCs were retained in the gastrocnemius muscle for 7 days after the injection, indicated by detection of GFP and expression of platelet-derived growth factor receptor-alpha. The injection of MSCs increased the expression of satellite cell-related genes, activated mTORC1 signaling and muscle protein synthesis, and increased protein ubiquitination and autophagosome formation (indicated by the expression of microtubule-associated protein 1 light chain 3-II). These results suggest that the intramuscular injection of MSCs activated muscle anabolic and catabolic systems and accelerated muscle protein turnover.
Skeletal muscle disuse rapidly decreases muscle mass. Resistance training (RT) is believed as the most effective way to gain muscle mass via an increase in mTORC1 activity and muscle protein ...synthesis (MPS). However, it remains unclear whether muscle atrophy by disuse alters the mTORC1 activation and MPS response to an acute resistance exercise (RE) and chronic RT–mediated skeletal muscle hypertrophy. This study investigated the influence of disuse muscle atrophy on the response of mTORC1 activation and MPS to an acute RE. We also evaluated whether disuse muscle atrophy affects the response of RT-induced muscle mass gain. Thirty male Sprague-Dawley rats were randomly divided into control (CON) or hindlimb suspension (HS) groups. A 14-day HS via the tail was used as the model for gastrocnemius muscle disuse in the HS group. Unilateral lower limb muscle contraction using by percutaneous electrical stimulation was used to mimic the stimuli of RE. Ten bouts of RE were performed in 3-week as chronic RT. Our results showed that MPS and mTORC1 activity was unchanged after HS at basal state. However, the ribosomal RNA (rRNA) level was reduced in HS rats compared to that in CON rats at basal state. MPS and rRNA increased in both HS and CON rats in response to acute RE to the same extent. However, the level of mTORC1 activation in response to an acute RE was significantly higher in HS than that in the CON group at 12 h after exercise, even though no difference was observed at 3 h after exercise. The 10-bout RT significantly increased gastrocnemius muscle mass in both CON and HS rats. The response of muscle hypertrophy did not differ between the groups. Therefore, MPS in response to acute RE and muscle hypertrophy in response to chronic RT were unaltered after disuse muscle atrophy.
Substantial evidence suggests an important role of liver function in brain health. Liver function is clinically assessed by measuring the activity of hepatic enzymes in the peripheral blood. ...Brain-derived neurotrophic factor (BDNF) is an important regulator of brain function. Therefore, we hypothesized that blood BDNF levels are associated with liver function and fibrosis. To test this hypothesis, in this cross-sectional study, we investigated whether serum BDNF concentration is associated with liver enzyme activity, aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ratio, and fibrosis-4 (FIB-4) index in middle-aged and older women. We found that serum BDNF level showed a significant positive association with ALT and γ-glutamyltranspeptidase (GGT) activity and negative association with FIB-4 index, and a trend of negative association with the AST/ALT ratio after adjustment for age. Additionally, these associations remained statistically significant even after adjustment for body mass index (BMI) and fasting blood glucose level. These results demonstrate associations of serum BDNF levels with liver enzymes and hepatic fibrosis-related indices, which may underlie liver-brain interactions.
Skeletal muscle mass is critical for activities of daily living. Resistance training maintains or increases muscle mass, and various strategies maximize the training adaptation. Mesenchymal stem ...cells (MSCs) are multipotent cells with differential potency in skeletal muscle cells and the capacity to secrete growth factors. However, little is known regarding the effect of intramuscular injection of MSCs on basal muscle protein synthesis and catabolic systems after resistance training. Here, we measured changes in basal muscle protein synthesis, the ubiquitin‐proteasome system, and autophagy‐lysosome system‐related factors after bouts of resistance exercise by intramuscular injection of MSCs. Mice performed three bouts of resistance exercise (each consisting of 50 maximal isometric contractions elicited by electrical stimulation) on the right gastrocnemius muscle every 48 h, and immediately after the first bout, mice were intramuscularly injected with either MSCs (2.0 × 106 cells) labeled with green fluorescence protein (GFP) or vehicle only placebo. Seventy‐two hours after the third exercise bout, GFP was detected only in the muscle injected with MSCs with concomitant elevation of muscle protein synthesis. The injection of MSCs also increased protein ubiquitination. These results suggest that the intramuscular injection of MSCs augmented muscle protein turnover at the basal state after consecutive resistance exercise.
In Japan, many workers are exposed to chronic stress, sleep deprivation, and nutritional imbalance. They tend still to go to work when ill, leading to decreased work performance and productivity, ...which has become a major social problem. We conducted a human entry study with the aim of finding a link between these two factors and proposing an optimized diet, believing that a review of diet may lead to an improvement in labor productivity. In this study, we used subjective accomplishment (SA) as a measure of productivity. First, we compared nutrient intake between groups with high and low SA using data from a health survey of 1564 healthy male and female adults. Significant differences were found in the intake of 13 nutrients in males and 15 nutrients in females, including potassium, vitamin A, insoluble fiber, and biotin. Recommended daily intake of these nutrients was determined from survey data. Next, we designed test meals containing sufficient amounts of 17 nutrients and conducted a single-arm intervention study (registration code UMIN000047054) in Kameyama City, Mie Prefecture, Japan. Healthy working adults (males and females aged 20-79 years) were recruited and supplied with test meals, which were eaten once a day 5 days a week for 8 weeks. SA was significantly higher and daytime sleepiness (DS) was significantly lower after lunch on workdays in younger participants (under 60 years) when they ate the test meals as breakfast or lunch. Our results suggest that SA and DS, which change daily, are strongly influenced by the meal eaten before work, and that taking the 17 nutrients may help prevent presenteeism and improve labor productivity.
A novel method to predict multi-atom cooperative phenomena at atomic scale is proposed based on a deep generative model in combination with recurrent neural network. The variational autoencoder (VAE) ...model successfully identifies three different crystal orientations in the polycrystalline nickel by using 10-dimensional latent variables and restores the image of atomic configurations reflecting the crystal orientation of each grain. Moreover, microstructure evolution of the polycrystalline iron is successfully predicted through three steps: dimensionality reduction of atomic coordinates from the MD simulation using the encoder, time evolution of latent variables using the long short-term memory (LSTM) model, and data restoration using the decoder. We successfully predict the microstructure that cannot be reproduced on the time scale of MD simulations by decoding latent variables in the future time from the LSTM model. This is a new attempt of acceleration of the MD simulation that differs significantly from conventional acceleration methods.
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Resistance exercise transiently activates anabolic and catabolic systems in skeletal muscle. Leucine-enriched essential amino acids (LEAAs) are reported to stimulate the muscle anabolic response at a ...lower dose than whey protein. However, little is known regarding the effect of LEAA supplementation on the resistance exercise-induced responses of the anabolic and catabolic systems. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparison trial to investigate the effect of LEAA supplementation on mechanistic target of rapamycin complex 1 (mTORC1), the ubiquitin-proteasome system and inflammatory cytokines after a single bout of resistance exercise in young men. A total of 20 healthy young male subjects were supplemented with either 5 g of LEAA or placebo, and then they performed 10 reps in three sets of leg extensions and leg curls (70% one-repetition maximum). LEAA supplementation augmented the phosphorylation of mTOR
(+77.1%,
< 0.05), p70S6K
(+1067.4%,
< 0.05), rpS6
(+171.3%,
< 0.05) and 4EBP1
(+33.4%,
< 0.05) after resistance exercise. However, LEAA supplementation did not change the response of the ubiquitinated proteins, MuRF-1 and Atrogin-1 expression. Additionally, the mRNA expression of IL-1β and IL-6 did not change. These data indicated that LEAA supplementation augments the effect of resistance exercise by enhancing mTORC1 signal activation after exercise.
Resistance exercise (RE) activates the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway and increases muscle protein synthesis. Severe fasting induces 5′ adenosine ...monophosphate‐activated protein kinase (AMPK), which attenuates mTORC1 activation. However, the effect of RE on the response of mTORC1 signaling proteins after a period of severe fasting is unclear. We investigated the effect of RE on rat skeletal muscle protein metabolism after a period of severe fasting. We hypothesized that RE‐induced activation of mTORC1 signaling protein attenuates protein breakdown by autophagy. Male Sprague‐Dawley rats were divided into ordinary‐fed (C) and 72‐h fasting (F) groups. A bout of RE was replicated by percutaneous electrical stimulation in the right gastrocnemius muscle. The tuberous sclerosis complex 2 (TSC2) Ser1387 and autophagy marker of microtubule‐associated protein 1A/1B‐light chain 3‐II (LC3B‐II) expression of the F group increased twice that of the C group in sedentary state (P < 0.05). RE activated the mTORC1 signaling pathway in both groups (P < 0.05); however, in the F group, the magnitude of p70S6K (Thr389) phosphorylation was lower by 40% of that of the C group (P < 0.05). Protein synthesis after RE was increased by 50% from the level at sedentary state in the C group (P < 0.05), but not in the F. In the F group, the expression of LC3B‐II at 3 h after RE was decreased by almost 25% from the level at sedentary state (P < 0.05). Our results suggest that RE suppressed fasting‐induced autophagy but did not increase protein synthesis during severe fasting in rat skeletal muscle.
Resistance exercise‐induced skeletal muscle protein synthesis does not occur during a severe fasting.
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