Publications by authors named "Satoru Ato"

21 Publications

  • Page 1 of 1

Basal and resistance exercise-induced increase in protein synthesis is impaired in skeletal muscle of iron-deficient rats.

Nutrition 2021 Jun 12;91-92:111389. Epub 2021 Jun 12.

Laboratory of Exercise Nutrition, Department of Nutrition, University of Shiga Prefecture, Japan.

Objectives: We aimed to investigate the effect of iron deficiency on basal- and contraction-induced increases in muscle protein synthesis.

Methods: Four-wk-old male Sprague-Dawley rats were divided into three groups. The rats in two of the three groups had free access to a control diet (AD) or iron-deficient diet (ID) for 4 wk. The rats in the third group (CON) were pair-fed the control diet to the mean intake of the ID group.

Results: In comparison with the CON group, the ID group showed significantly lower hematocrit and hemoglobin concentrations, iron-containing protein levels, and total iron content in skeletal muscle, but non-iron-containing protein levels did not show any differences between the groups. Protein synthesis, measured by puromycin-labeled peptides, was lower in the ID group compared with the CON group in both basal- and contraction-stimulated states. The ID diet impaired the activation levels of signaling pathways involved in protein synthesis, such as ribosomal protein S6 and eukaryotic translation initiation factor 4E-binding protein 1. Furthermore, dietary iron deficiency decreased autophagy capacity, but did not affect the ubiquitinated protein content.

Conclusions: These results suggest that severe iron deficiency decreases not only basal but also muscle contraction-induced increases in protein synthesis due to, at least in part, downregulation of the protein synthesis signaling pathway in the skeletal muscle.
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http://dx.doi.org/10.1016/j.nut.2021.111389DOI Listing
June 2021

Short-term high-fat diet induces muscle fiber type-selective anabolic resistance to resistance exercise.

J Appl Physiol (1985) 2021 Aug 17;131(2):442-453. Epub 2021 Jun 17.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan.

Chronic obesity and insulin resistance are considered to inhibit contraction-induced muscle hypertrophy, through impairment of mammalian target of rapamycin complex 1 (mTORC1) and muscle protein synthesis (MPS). A high-fat diet is known to rapidly induce obesity and insulin resistance within a month. However, the influence of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute resistance exercise (RE) is unclear. Thus the purpose of this study was to investigate the effect of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute RE. Male Sprague-Dawley rats were randomly assigned to groups and fed a normal diet, high-fat diet, or pair feed for 4 wk. After dietary habituation, acute RE was performed on the gastrocnemius muscle via percutaneous electrical stimulation. The results showed that 4 wk of a high fat-diet induced intramuscular lipid accumulation and insulin resistance, without affecting basal mTORC1 activity or MPS. The response of RE-induced mTORC1 activation and MPS was not altered by a high-fat diet. On the other hand, analysis of each fiber type demonstrated that response of MPS to an acute RE was disappeared specifically in type I and IIa fiber. These results indicate that a short-term high-fat diet causes anabolic resistance to acute RE, depending on the fiber type. A high-fat diet is known to rapidly induce obesity, insulin resistance, and anabolic resistance to nutrition within a month. However, the influence of a short-term high-fat diet on the response of muscle protein synthesis to acute resistance exercise is unclear. We observed that a short-term high-fat diet causes obesity, insulin resistance, intramuscular lipid droplet accumulation, and anabolic resistance to resistance exercise specifically in type I and IIa fibers.
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http://dx.doi.org/10.1152/japplphysiol.00889.2020DOI Listing
August 2021

The relationship between myonuclear number and protein synthesis in individual rat skeletal muscle fibres.

J Exp Biol 2021 05 18;224(10). Epub 2021 May 18.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Showa-ku, Nagoya 466-8555, Japan.

Skeletal muscle has numerous nuclei within a cell. The nucleus is considered as the central organelle for muscle protein synthesis (MPS). However, it is unclear whether myonuclear number is associated with MPS capacity within the individual muscle fibres. Therefore, the purpose of the present study was to reveal the relationship between myonuclear number per unit muscle fibre length and MPS under basal and conditions of elevated MPS by high-intensity muscle contraction (HiMC) using an in vivo nascent protein labelling technique (SUnSET) in rodents. We found that myonuclear number was positively correlated with MPS in individual muscle fibres in the basal condition. Similarly, ribosomal protein S6 (rpS6) content, which is a rough estimate of ribosome content, was positively correlated with MPS. However, myonuclear number was not associated with rpS6 content. In contrast to the basal condition, when MPS was increased by acute HiMC, no correlation was observed between myonuclear number and MPS, but the association between rpS6 and MPS was maintained. Importantly, these observations indicate that the number of nuclei in individual myofibers is related only to MPS at rest. However, the ribosome content in individual fibres is related to MPS of individual myofibers both at rest and following HiMC.
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http://dx.doi.org/10.1242/jeb.242496DOI Listing
May 2021

Effect of 2-deoxyglucose-mediated inhibition of glycolysis on the regulation of mTOR signaling and protein synthesis before and after high-intensity muscle contraction.

Metabolism 2021 01 5;114:154419. Epub 2020 Nov 5.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan. Electronic address:

Background: Glycolysis controls mTORC1 signaling and protein synthesis. In skeletal muscle, glucose metabolism increases with both exercise/contraction intensity and volume, and therefore, high-intensity muscle contraction (HiMC) such as resistance exercise facilitates glycolysis including glucose uptake and glycogen breakdown. However, it is unknown whether glycolysis regulates HiMC-induced mTORC1 activation and increase in protein synthesis.

Methods: To determine whether glycolysis regulates basal and HiMC-induced mTORC1 signaling and protein synthesis, we employed 2-deoxyglucose (2-DG) to inhibit glycolysis and isometrically contracted the gastrocnemius muscle of Sprague Dawley rats using percutaneous electrical stimulation.

Results: Inhibition of glycolysis by 2-DG inhibited basal phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTORC1) and protein synthesis (all P < 0.05) independent of AMPK phosphorylation. AMPK phosphorylation was comparably increased after HiMC at 0 h post HiMC and returned to basal levels 6 h post HiMC in both vehicle- and 2-DG-treated groups. Glycolysis inhibition attenuated muscle contraction-induced phosphorylation of 4E-BP1 at 6 h post HiMC (P < 0.05) but not p70S6K phosphorylation and protein synthesis.

Conclusion: Although glycolysis is involved in basal but not HiMC-induced muscle protein synthesis, it regulates both basal and HiMC-induced mTORC1 signaling, and may play key roles in skeletal muscle adaptation to HiMC.
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http://dx.doi.org/10.1016/j.metabol.2020.154419DOI Listing
January 2021

Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated muscle protein synthesis.

J Physiol 2020 12 23;598(23):5453-5466. Epub 2020 Sep 23.

Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.

Key Points: Muscle contractions increase protein synthesis in a mechanistic target of rapamycin (mTOR)-dependent manner, yet it is unclear which/how mTOR complexes regulate muscle protein synthesis. We investigated the requirement of mTOR Complex 2 (mTORC2) in contraction-stimulated muscle protein synthesis. mTORC2 inhibition by muscle-specific Rictor knockout (Rictor mKO) did not prevent contraction-induced muscle protein synthesis. Rapamycin prevented contraction-induced muscle protein synthesis in Rictor mKO but not wild-type mice.

Abstract: Protein synthesis increases following muscle contractions. Previous studies have shown that inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) suppresses the early but not late muscle protein synthesis response, while inhibition of both mTORC1 and mTORC2 abolishes the two effects. Therefore, we hypothesized that mTORC2 regulates muscle protein synthesis following muscle contractions. To test this, we investigated the effect of mTORC2 inhibition by mouse muscle-specific Rictor knockout (Rictor mKO) on muscle protein synthesis 3 h after contraction. The right gastrocnemius muscles of Rictor mKO and wild-type (WT) mice were isometrically contracted using percutaneous electrical stimulation, while the left gastrocnemius muscles served as controls. Vehicle or the mTORC1 inhibitor rapamycin (1.5 mg/kg) was injected intraperitoneally 1 h before contraction. Treatment of WT mice with rapamycin and Rictor mKO lowered protein synthesis in general, but the response to contractions was intact 3 h after contractions in both conditions. Rapamycin treatment in Rictor mKO mice prevented contraction-stimulated muscle protein synthesis. Notably, signalling traditionally associated with mTORC1 was increased by muscle contractions despite rapamycin treatment. In rapamycin-treated Rictor mKO mice, the same mTORC1 signalling was blocked following contractions. Our results indicate that although neither rapamycin-sensitive mTOR/mTORC1 nor mTORC2 is necessary for contraction-induced muscle protein synthesis, combined inhibition of rapamycin-sensitive mTOR/mTORC1 and mTORC2 synergistically inhibits contraction-induced muscle protein synthesis.
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http://dx.doi.org/10.1113/JP280528DOI Listing
December 2020

Response of Resistance Exercise-Induced Muscle Protein Synthesis and Skeletal Muscle Hypertrophy Are Not Enhanced After Disuse Muscle Atrophy in Rat.

Front Physiol 2020 21;11:469. Epub 2020 May 21.

Graduate School of Sport and Health Science, Ritsumeikan University, Shiga, Japan.

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.
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http://dx.doi.org/10.3389/fphys.2020.00469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258402PMC
May 2020

Habitual high-protein diet does not influence muscle protein synthesis in response to acute resistance exercise in rats.

Nutrition 2020 10 5;78:110795. Epub 2020 Mar 5.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan. Electronic address:

Objectives: Resistance training combined with consumption of a high-protein diet (HPD) is typically recommended to increase muscle mass, as both acute resistance exercise (RE) and dietary protein intake stimulate mechanistic target of rapamycin complex 1 (mTORC1) and muscle protein synthesis (MPS). However, the effect of chronic HPD consumption on MPS response to an acute RE remains to be determined.

Methods: Male Sprague-Dawley rats aged 10 wk were fed HPD (50 kcal % protein, for 4 wk) or normal protein diet (NPD; 20 kcal % protein). After the 4-wk dietary intervention, the rats were fasted overnight and the right gastrocnemius muscle was subjected to percutaneous electrical stimulation to mimic acute RE, whereas the left gastrocnemius muscle served as control. The rats were sacrificed 6 h after exercise and the tissues were sampled immediately.

Results: The HPD group showed significantly lower fat mass and higher skeletal muscle mass than the NPD group without affecting body weight. Resting mTORC1 activity did not differ between the groups. Additionally, resting MPS was also unchanged after HPD. Acute RE significantly increased mTORC1 activity and MPS in both groups. However, differences in diet did not influence the response of mTORC1 activation to acute RE. Furthermore, HPD did not affect the response of MPS to acute RE.

Conclusion: The present results suggested that although 4 wk of HPD reduces body fat and increases skeletal muscle mass, it does not affect muscle protein synthesis at basal state, and in response to acute RE.
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http://dx.doi.org/10.1016/j.nut.2020.110795DOI Listing
October 2020

High-intensity muscle contraction-mediated increases in Akt1 and Akt2 phosphorylation do not contribute to mTORC1 activation and muscle protein synthesis.

J Appl Physiol (1985) 2020 04 20;128(4):830-837. Epub 2020 Feb 20.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan.

High-intensity muscle contraction (HiMC) is known to induce muscle protein synthesis, a process in which mechanistic target of rapamycin (mTOR) is reported to play a critical role. However, the mechanistic details have not been completely elucidated. Here, we investigated whether Akt plays a role in regulating HiMC-induced mTORC1 activation and muscle protein synthesis using a rodent model of resistance exercise and MK2206 (an Akt kinase inhibitor). The right gastrocnemius muscle of male C57BL/6J mice aged 10 wk was isometrically contracted via percutaneous electrical stimulation (100 Hz, 5 sets of 10 3-s contractions, 7-s rest between contractions, and 3-min rest between sets), while the left gastrocnemius muscle served as a control. Vehicle or MK2206 was injected intraperitoneally 6 h before contraction. MK2206 inhibited both resting and HiMC-induced phosphorylation of Akt1 Ser-473 and Akt2 Ser-474. MK2206 also inhibited the resting phosphorylation of p70S6K and 4E-BP1, which are downstream targets of mTORC1; however, it did not inhibit the HiMC-induced increase in phosphorylation of these targets. Similarly, MK2206 inhibited the resting muscle protein synthesis, but not the resistance exercise-induced muscle protein synthesis. On the basis of these observations, we conclude that although Akt2 regulates resting mTORC1 activity and muscle protein synthesis, HiMC-induced increases in mTORC1 activity and muscle protein synthesis are Akt-independent processes. Akt is well known to be an upstream regulator of mechanistic target of rapamycin (mTOR) and has three isoforms in mammals, namely, Akt1, Akt2, and Akt3. We found that high-intensity muscle contraction (HiMC) increases Akt1 and Akt2 phosphorylation; however, HiMC-induced increases in mTORC1 activity and muscle protein synthesis are Akt-independent processes.
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http://dx.doi.org/10.1152/japplphysiol.00578.2019DOI Listing
April 2020

Dietary Aronia melanocarpa extract enhances mTORC1 signaling, but has no effect on protein synthesis and protein breakdown-related signaling, in response to resistance exercise in rat skeletal muscle.

J Int Soc Sports Nutr 2019 Dec 11;16(1):60. Epub 2019 Dec 11.

Ritsumeikan Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Shiga, Japan.

Background: Ursolic acid altered muscle protein metabolism in normal and resting conditions after acute resistance exercise, suggesting that eating fruits rich in ursolic acid could enhance muscle protein synthesis and decrease muscle degradation. Aronia melanocarpa, a member of the family Rosaceae and native to North America and Eastern Canada, is rich in ursolic acid. In this study, we examined the effects of A. melanocarpa extract (AME) supplementation on the mTORC1 signaling pathway and muscle degradation-related factors in rats, both alone and in combination with resistance exercise.

Methods: Male Sprague-Dawley rats were divided into AME and normal chow (NOR) groups. AME group was fed chow providing a dose of 3 g/kg of AME and 115 mg/kg of ursolic acid for 7 days, whereas NOR rats were fed normal powder chow. The right gastrocnemius muscle of each animal was isometrically exercised (5 sets of ten 3-s contractions, with a 7-s interval between contractions and 3-min rest intervals between sets), while the left gastrocnemius muscle served as an internal control. Western blotting and real-time polymerase chain reaction were used to assess expression of factors involved in the mTORC1 signaling pathway and muscle degradation.

Results: At 1 h after resistance exercise, phosphorylation of ERK1/2 was significantly increased by AME consumption. At 6 h after resistance exercise, AME consumption significantly increased the phosphorylation of Akt, p70S6K, rpS6, and AMPK. It also increased MAFbx expression. Furthermore, AME significantly increased the phosphorylation of p70S6K and rpS6 in response to resistance exercise. However, AME did not increase muscle protein synthesis (MPS) after resistance exercise. AME did not affect the expression of any of the mediators of protein degradation, with the exception of MAFbx.

Conclusions: Dietary AME enhanced mTORC1 activation in response to resistance exercise without increasing MPS. Moreover, it neither accelerated muscle protein degradation nor otherwise negatively affected protein metabolism. Further study is needed to clarify the effect of the combination of AME and chronic resistance training on muscle hypertrophy.
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http://dx.doi.org/10.1186/s12970-019-0328-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907222PMC
December 2019

The effect of a bout of resistance exercise on skeletal muscle protein metabolism after severe fasting.

Physiol Rep 2019 11;7(21):e14270

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan.

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.
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http://dx.doi.org/10.14814/phy2.14270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831946PMC
November 2019

Type 2 diabetes causes skeletal muscle atrophy but does not impair resistance training-mediated myonuclear accretion and muscle mass gain in rats.

Exp Physiol 2019 10 13;104(10):1518-1531. Epub 2019 Aug 13.

Graduate School of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan.

New Findings: What is the central question of this study? Type 2 diabetes mellitus (T2DM) causes skeletal muscle atrophy; does it affect resistance training (RT)-mediated molecular adaptations and subsequent muscle hypertrophy? What is the main finding and its importance? Although skeletal muscle mass and regulation were not preserved under conditions of T2DM, the response of RT-induced skeletal muscle hypertrophy was not impaired in T2DM rat skeletal muscle. These findings suggest that the capacity of RT-mediated muscle mass gain is not diminished in the T2DM condition.

Abstract: Type 2 diabetes mellitus (T2DM) is known to cause skeletal muscle atrophy. However, it is not known whether T2DM affects resistance training (RT)-mediated molecular adaptations and subsequent muscle hypertrophy. Therefore, we investigated the effect of T2DM on response of skeletal muscle hypertrophy to chronic RT using a rat resistance exercise mimetic model. T2DM and healthy control rats were subjected to 18 bouts (3 times per week) of chronic RT on unilateral lower legs. RT significantly increased gastrocnemius muscle mass and myonuclei in both T2DM and healthy control rats to the same extent, even though T2DM caused muscle atrophy in the resting condition. Further, T2DM significantly reduced mechanistic target of rapamycin complex 1 (mTORC1) activity (phosphorylation of p70S6K and 4E-BP1 ) to insulin stimulation and the number of myonuclei in the untrained basal condition, but RT-mediated adaptations were not affected by T2DM. These findings suggested that although the skeletal muscle mass and regulation were not preserved under basal conditions of T2DM, the response of RT-induced skeletal muscle hypertrophy was not impaired in T2DM rat skeletal muscle.
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http://dx.doi.org/10.1113/EP087585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790689PMC
October 2019

The Effect of Changing the Contraction Mode During Resistance Training on mTORC1 Signaling and Muscle Protein Synthesis.

Front Physiol 2019 18;10:406. Epub 2019 Apr 18.

Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan.

Acute resistance exercise (RE) increases muscle protein synthesis (MPS) via activation of mechanistic target of rapamycin complex (mTORC), and chronic resistance exercise training (RT) results in skeletal muscle hypertrophy. Although MPS in response to RE is blunted over time during RT, no effective restorative strategy has been identified. Since eccentric muscle contraction (EC) has the potential to strongly stimulate mTORC1 activation and MPS, changing the muscle contraction mode to EC might maintain the MPS response to RE during chronic RT. Male rats were randomly divided into RE (1 bout of RE) and RT (13 bouts of RE) groups. Additionally, each group was subdivided into isometric contraction (IC) and EC subgroups. The RE groups performed acute, unilateral RE using IC or EC. The RT groups performed 12 bouts of unilateral RE using IC. For bout 13, the RT-IC subgroup performed a further IC bout, while the RT-EC subgroup changed to EC. All muscle contractions were induced by percutaneous electrical stimulation. Muscle samples were obtained at 6 h post exercise in all groups. After the 1st RE bout, the EC group showed significantly higher p70S6K Thr389 phosphorylation than the IC group. However, the phosphorylation of other mTORC1-associated proteins (4E-BP1 and ribosomal protein S6) and the MPS response did not differ between the contraction modes. After the 13th bout of RE, mTORC1 activation and the MPS response were significantly blunted as compared with the 1st bout of RE. Changing from IC to EC did not improve these responses. In conclusion, changing the contraction mode to EC does not reinvigorate the blunted mTORC1 activation and MPS in response to RE during chronic RT.
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http://dx.doi.org/10.3389/fphys.2019.00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482468PMC
April 2019

The effects of resistance training on bone mineral density and bone quality in type 2 diabetic rats.

Physiol Rep 2019 03;7(6):e14046

Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Ehime, Japan.

Resistance training (RT) has been known to be effective in maintaining and improving bone strength, which is based on bone mineral density (BMD) and bone quality. However, it is not clear whether RT is effective in improving bone strength in patients with type-2 diabetes mellitus (T2DM), who have a high risk of fracture. Therefore, we tested the effects of a 6-week RT regimen using percutaneous electrical stimulation in T2DM model rats, male Otsuka Long-Evans Tokushima Fatty (OLETF), and its control, Long-Evans Tokushima Otsuka (LETO). After 6 weeks of RT, tibial BMD in RT legs was significantly higher than that in control (CON) legs in both groups. In diaphyseal cortical bone, bone area/tissue area, and cortical thickness was significantly increased in RT legs compared with CON legs in both groups. Cortical porosity was highly observed in OLETF compared with LETO, but RT improved cortical porosity in both groups. Interestingly, trabecular number, trabecular thickness and trabecular space as well as BMD and bone volume/tissue volume in proximal tibial metaphyseal trabecular bone were significantly improved in RT legs compared with CON legs in both groups. In contrast, connectivity density and structural model index were not affected by RT. These results indicate that the 6-week RT regimen effectively increased BMD and improved bone quality in T2DM model rats as well as control rats. Therefore, RT may have the potential to improve bone strength and reduce fracture risk, even in patients with T2DM.
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http://dx.doi.org/10.14814/phy2.14046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436184PMC
March 2019

Chemical denervation using botulinum toxin increases Akt expression and reduces submaximal insulin-stimulated glucose transport in mouse muscle.

Cell Signal 2019 01 21;53:224-233. Epub 2018 Oct 21.

Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark. Electronic address:

Botulinum toxin A (botox) is a toxin used for spasticity treatment and cosmetic purposes. Botox blocks the excitation of skeletal muscle fibers by preventing the release of acetylcholine from motor nerves, a process termed chemical denervation. Surgical denervation is associated with increased expression of the canonical insulin-activated kinase Akt, lower expression of glucose handling proteins GLUT4 and hexokinase II (HKII) and insulin resistant glucose uptake, but it is not known if botox has a similar effect. To test this, we performed a time-course study using supra-maximal insulin-stimulation in mouse soleus ex vivo. No effect was observed in the glucose transport responsiveness at day 1, 7 and 21 after intramuscular botox injection, despite lower expression of GLUT4, HKII and expression and phosphorylation of TBC1D4. Akt protein expression and phosphorylation of the upstream kinase Akt were increased by botox treatment at day 21. In a follow-up study, botox decreased submaximal insulin-stimulated glucose transport. The marked alterations of insulin signaling, GLUT4 and HKII and submaximal insulin-stimulated glucose transport are a potential concern with botox treatment which merit further investigation in human muscle. Furthermore, the botox-induced chemical denervation model may be a less invasive alternative to surgical denervation.
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http://dx.doi.org/10.1016/j.cellsig.2018.10.014DOI Listing
January 2019

Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats.

Am J Physiol Endocrinol Metab 2018 06 6;314(6):E564-E571. Epub 2018 Feb 6.

Faculty of Sport and Health Science, Ritsumeikan University , Kusatsu , Japan.

Adapter protein containing Pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (APPL1) has been reported as a positive regulator of insulin-stimulated Akt activation. The expression of APPL1 is reduced in skeletal muscles of type 2 diabetic (T2D) animals, implying that APPL1 may be an important factor affecting insulin sensitivity. However, the regulation of APPL1 expression and the physiological interventions modulating these effects are unclear. Accordingly, we first confirmed that APPL1 expression and insulin-induced Akt phosphorylation were significantly attenuated in skeletal muscles of T2D rats. Additionally, we found that APPL1 expression levels were significantly correlated with fasting blood glucose levels. Next, we identified important signals involved in the expression of APPL1. APPL1 mRNA expression increased upon AMP-activated protein kinase, calcium, p38 mitogen-activated protein kinase, and insulin-like growth factor-1 signal activation. Moreover, acute resistance exercise in vivo significantly activated these signaling pathways. Finally, through in vivo experiments, we found that chronic resistance training (RT) increased APPL1 expression and activated insulin-induced Akt signaling in skeletal muscles of rats with T2D. Furthermore, variations in APPL1 expression (i.e., the difference between control and RT muscles) significantly correlated with variations in insulin-stimulated Akt phosphorylation under the same conditions. Therefore, chronic RT recovered attenuated APPL1 expression and improved insulin-stimulated Akt phosphorylation in skeletal muscles of T2D rats. Accordingly, APPL1 may be a key regulator of insulin resistance in skeletal muscle, and RT may be an important physiological treatment increasing APPL1 expression, which is attenuated in T2D.
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http://dx.doi.org/10.1152/ajpendo.00362.2017DOI Listing
June 2018

The effect of different acute muscle contraction regimens on the expression of muscle proteolytic signaling proteins and genes.

Physiol Rep 2017 Aug;5(15)

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan

Previous studies have reported that different modes of muscle contraction (i.e., eccentric or concentric contraction) with similar contraction times can affect muscle proteolytic responses. However, the effect of different contraction modes on muscle proteolytic response under the same force-time integral (FTI: contraction force × time) has not been investigated. The purpose of this study was to investigate the effect of different contraction modes, with the same FTI, on acute proteolytic signaling responses. Eleven-week-old male Sprague-Dawley rats were randomly assigned to eccentric (EC), concentric (CC), or isometric contraction (IC) groups. Different modes of muscle contraction were performed on the right gastrocnemius muscle using electrical stimulation, with the left muscle acting as a control. In order to apply an equivalent FTI, the number of stimulation sets was modified between the groups. Muscle samples were taken immediately and three hours after exercise. Phosphorylation of FoxO3a at Ser253 was significantly increased immediately after exercise compared to controls irrespective of contraction mode. The mRNA levels of the ubiquitin ligases, MuRF1, and MAFbx mRNA were unchanged by contraction mode or time. Phosphorylation of ULK1 at Ser317 (positive regulatory site) and Ser757 (negative regulatory site) was significantly increased compared to controls, immediately or 3 h after exercise, in all contraction modes. The autophagy markers (LC3B-II/I ratio and p62 expression) were unchanged, regardless of contraction mode. These data suggest that differences in contraction mode during resistance exercise with a constant FTI, are not factors in regulating proteolytic signaling in the early phase of skeletal muscle contraction.
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http://dx.doi.org/10.14814/phy2.13364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555890PMC
August 2017

Effect of resistance exercise under conditions of reduced blood insulin on AMPKα Ser485/491 inhibitory phosphorylation and AMPK pathway activation.

Am J Physiol Regul Integr Comp Physiol 2017 Aug 17;313(2):R110-R119. Epub 2017 May 17.

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan;

Insulin stimulates skeletal muscle glucose uptake via activation of the protein kinase B/Akt (Akt) pathway. Recent studies suggest that insulin downregulates AMP-activated protein kinase (AMPK) activity via Ser485/491 phosphorylation of the AMPK α-subunit. Thus lower blood insulin concentrations may induce AMPK signal activation. Acute exercise is one method to stimulate AMPK activation; however, no study has examined the relationship between blood insulin levels and acute resistance exercise-induced AMPK pathway activation. Based on previous findings, we hypothesized that the acute resistance exercise-induced AMPK pathway activation would be augmented by disruptions in insulin secretion through a decrease in AMPKα Ser485/491 inhibitory phosphorylation. To test the hypothesis, 10-wk-old male Sprague-Dawley rats were administered the toxin streptozotocin (STZ; 55 mg/kg) to destroy the insulin secreting β-cells. Three days postinjection, the right gastrocnemius muscle from STZ and control rats was subjected to resistance exercise by percutaneous electrical stimulation. Animals were killed 0, 1, or 3 h later; activation of the Akt/AMPK and downstream pathways in the muscle tissue was analyzed by Western blotting and real-time PCR. Notably, STZ rats showed a significant decrease in basal Akt and AMPKα Ser485/491 phosphorylation, but substantial exercise-induced increases in both AMPKα Thr172 and acetyl-CoA carboxylase (ACC) Ser79 phosphorylation were observed. Although no significant impact on resistance exercise-induced Akt pathway activation or glucose uptake was found, resistance exercise-induced peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 α (PGC-1α) gene expression was augmented by STZ treatment. Collectively, these data suggest that circulating insulin levels may regulate acute resistance exercise-induced AMPK pathway activation and AMPK-dependent gene expression relating to basal AMPKα Ser485/491 phosphorylation.
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http://dx.doi.org/10.1152/ajpregu.00063.2017DOI Listing
August 2017

Panaxatriol derived from ginseng augments resistance exercised-induced protein synthesis via mTORC1 signaling in rat skeletal muscle.

Nutr Res 2016 11 13;36(11):1193-1201. Epub 2016 Sep 13.

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan. Electronic address:

Resistance exercise activates muscle protein synthesis via the mammalian target of rapamycin complex 1 (mTORC1) pathway and subsequent muscle hypertrophy. Upstream components of the mTORC1 pathway are widely known to be involved in Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Previous studies have shown that ginseng stimulated Akt and ERK1/2 signaling. Therefore, we hypothesized that panaxatriol (PT) derived from ginseng triggers mTORC1 signaling and muscle protein synthesis by activating both the Akt and ERK1/2 signaling pathways, and that PT additively stimulates muscle protein synthesis when combined with resistance exercise. The study included male Sprague-Dawley rats. The legs of the rats were divided into control, PT-only, exercise-only, and exercise + PT groups. The right legs were subjected to isometric resistance exercise using percutaneous electrical stimulation, whereas the left legs were used as controls. PT (0.2 g/kg) was administered immediately after exercise. The Akt and ERK1/2 phosphorylation levels were significantly higher in the exercise + PT group than in the exercise-only group 0.5 hour after exercise. The phosphorylation of p70S6K was significantly increased at both 0.5 and 3 hours after exercise, and it was higher in the exercise + PT group than in the exercise-only group at both 0.5 and 3 hours after exercise. Muscle protein synthesis was significantly increased 3 hours after exercise, and it was higher in the exercise + PT group than in the exercise-only group 3 hours after exercise. Our results suggest that PT derived from ginseng enhances resistance exercise-induced protein synthesis via mTORC1 signaling in rat skeletal muscle.
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http://dx.doi.org/10.1016/j.nutres.2016.09.002DOI Listing
November 2016

Contraction mode itself does not determine the level of mTORC1 activity in rat skeletal muscle.

Physiol Rep 2016 10;4(19)

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan

Resistance training with eccentric contraction has been shown to augment muscle hypertrophy more than other contraction modes do (i.e., concentric and isometric contraction). However, the molecular mechanisms involved remain unclear. The purpose of this study was to investigate the effect of muscle contraction mode on mammalian target of rapamycin complex 1 (mTORC1) signaling using a standardized force-time integral (load (weight) × contraction time). Male Sprague-Dawley rats were randomly assigned to three groups: eccentric contraction, concentric contraction, and isometric contraction. The right gastrocnemius muscle was exercised via percutaneous electrical stimulation-induced maximal contraction. In experiment 1, different modes of muscle contraction were exerted using the same number of reps in all groups, while in experiment 2, muscle contractions were exerted using a standardized force-time integral. Muscle samples were obtained immediately and 3 h after exercise. Phosphorylation of molecules associated with mTORC1 activity was assessed using western blot analysis. In experiment 1, the force-time integral was significantly different among contraction modes with a higher force-time integral for eccentric contraction compared to that for other contraction modes (P < 0.05). In addition, the force-time integral was higher for concentric contraction compared to that for isometric contraction (P < 0.05). Similarly, p70S6K phosphorylation level was higher for eccentric contraction than for other modes of contraction (P < 0.05), and concentric contraction was higher than isometric contraction (P < 0.05) 3 h after exercise. In experiment 2, under the same force-time integral, p70S6K (Thr389) and 4E-BP1 phosphorylation levels were similar among contraction modes 3 h after exercise. Our results suggest that mTORC1 activity is not determined by differences in muscle contraction mode itself. Instead, mTORC1 activity is determined by differences in the force-time integral during muscle contraction.
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http://dx.doi.org/10.14814/phy2.12976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064134PMC
October 2016

Acute resistance exercise-induced IGF1 expression and subsequent GLUT4 translocation.

Physiol Rep 2016 08;4(16)

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan

Acute aerobic exercise (AE) is a major physiological stimulus for skeletal muscle glucose uptake through activation of 5' AMP-activated protein kinase (AMPK). However, the regulation of glucose uptake by acute resistance exercise (RE) remains unclear. To investigate the intracellular regulation of glucose uptake after acute RE versus acute AE, male Sprague-Dawley rats were divided into three groups: RE, AE, or nonexercise control. After fasting for 12 h overnight, the right gastrocnemius muscle in the RE group was exercised at maximum isometric contraction via percutaneous electrical stimulation (3 × 10 sec, 5 sets). The AE group ran on a treadmill (25 m/min, 60 min). Muscle samples were taken 0, 1, and 3 h after completion of the exercises. AMPK, Ca(2+)/calmodulin-dependent protein kinase II, and TBC1D1 phosphorylation were increased immediately after both forms of exercise and returned to baseline levels by 3 h. Muscle IGF1 expression was increased by RE but not AE, and maintained until 3 h after RE Additionally, Akt and AS160 phosphorylation were sustained for 3 h after RE, whereas they returned to baseline levels by 3 h after AE Similarly, GLUT4 translocation remained elevated 3 h after RE, although it returned to the baseline level by 3 h after AE Overall, this study showed that AMPK/TBC1D1 and IGF1/Akt/AS160 signaling were enhanced by acute RE, and that GLUT4 translocation after acute RE was more prolonged than after acute AE These results suggest that acute RE-induced increases in intramuscular IGF1 expression might be a distinct regulator of GLUT4 translocation.
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http://dx.doi.org/10.14814/phy2.12907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002915PMC
August 2016

Herbal supplement Kamishimotsuto augments resistance exercise-induced mTORC1 signaling in rat skeletal muscle.

Nutrition 2016 Jan 22;32(1):108-13. Epub 2015 Jul 22.

Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan. Electronic address:

Objectives: Kamishimotsuto (KST) is a supplement containing 13 different herbs including Phellodendron bark, Anemarrhena rhizome and ginseng that have been shown to activate mammalian target of rapamycin complex 1 (mTORC1) and thereby increase muscle protein synthesis in vitro. However, the combined effect of KST and resistance exercise on muscle protein anabolism has not been investigated in vivo. Therefore, the purpose of this study was to investigate the effect of KST supplementation, resistance exercise on (mTORC1) signaling and subsequent muscle protein synthesis.

Methods: Male Sprague-Dawley rats were divided into two groups: one group received KST (500 mg/kg/d in water) and the other group received placebo (PLA) for 7 d. After 12 h of fasting, the right gastrocnemius muscle was isometrically exercised via percutaneous electrical stimulation. Muscle samples were analyzed for muscle protein synthesis (MPS) and by western blotting analysis to assess the phosphorylation of p70S6K (Thr389), rpS6 (Ser240/244), and Akt (Ser473 and Thr308).

Results: KST supplementation for 7 d significantly increased basal p-Akt (Ser473) levels compared with PLA, phosphorylation of the signaling proteins and MPS at baseline were otherwise unaffected. p-p70S6K and p-rpS6 levels significantly increased 1 h and 3 h after exercise in the PLA group, and these elevations were augmented in the KST group (P < 0.05). Furthermore, MPS at 6 h after resistance exercise was greater in the KST group than in the PLA group (P < 0.05).

Conclusions: While resistance exercise alone was able to increase p70S6K and rpS6 phosphorylation, Kamishimotsuto supplementation further augmented resistance exercise-induced muscle protein synthesis through mTORC1 signaling.
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http://dx.doi.org/10.1016/j.nut.2015.06.015DOI Listing
January 2016
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