Publications by authors named "Hidemi Fujino"

72 Publications

Nucleoprotein-enriched diet enhances the protein synthesis pathway and satellite cell activation via ERK1/2 phosphorylation in the unloaded rat muscle.

Exp Physiol 2021 Apr 20. Epub 2021 Apr 20.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan.

New Findings: What is the central question of this study? The purpose of this study was to determine if the nucleotides in a nucleoprotein diet could ameliorate the unloading-associated decrease in soleus muscle mass and fiber size. What is the main finding and its importance? The results indicate that the nucleotides in the nucleoprotein-enriched diet could ameliorate the unloading-associated decrease in type I fiber size and muscle mass most likely due to the activation of protein synthesis pathways and satellite cell proliferation and differentiation via ERK1/2 phosphorylation. Thus nucleotide supplementation appears to be an effective countermeasure for muscle atrophy.

Abstract: Hindlimb unloading decreases both protein synthesis pathway and satellite cell activation results in muscle atrophy. Nucleotides are included in nucleoprotein and provide the benefits of increasing ERK1/2 phosphorylation. ERK 1/2 phosphorylation is also important in the activation of satellite cells, especially for myoblast proliferation and stimulating protein synthesis pathways. Therefore, we hypothesized that nucleotide in the nucleoproteins would ameliorate muscle atrophy via increasing the protein synthesis pathways and satellite cell activation during hindlimb unloading in rat soleus. Twenty-four female Wistar rats were divided into four groups: control rats fed a basal diet without nucleoprotein (CON), control rats fed a nucleoprotein-enriched diet (CON+NP), hindlimb unloaded rats fed a basal diet (HU), or hindlimb unloaded rats fed a NP diet (HU+NP). HU for two-weeks resulted in decreases in p70S6K- and rpS6-phosphorylation, the numbers of MyoD and myogenin, type I muscle fiber size, and muscle mass. Both CON and HU rats fed the NP diet showed an increase in ERK1/2, p70S6K- and rpS6-phosphorylation, and in the number of MyoD and myogenin compared to their basal diet groups. The NP diet also ameliorated the unloading-associated decrease in type I muscle fiber size and muscle mass. The results indicate that the nucleotides in the nucleoprotein-enriched diet could ameliorate the unloading-associated decrease in type I fiber size and muscle mass most likely due to the activation of protein synthesis pathways and satellite cell proliferation and differentiation via ERK1/2 phosphorylation. Thus nucleotide supplementation appears to be an effective countermeasure for muscle atrophy. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/EP089337DOI Listing
April 2021

Reduced metabolic capacity in fast and slow skeletal muscle via oxidative stress and the energy-sensing of AMPK/SIRT1 in malnutrition.

Physiol Rep 2021 Mar;9(5):e14763

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

The effects of malnutrition on skeletal muscle result in not only the loss of muscle mass but also fatigue intolerance. It remains unknown whether the metabolic capacity is related to the fiber type composition of skeletal muscle under malnourished condition although malnutrition resulted in preferential atrophy in fast muscle. The purpose of the present study was to investigate the effects of metabolic capacity in fast and slow muscles via the energy-sensing of AMPK and SIRT1 in malnutrition. Wistar rats were randomly divided into control and malnutrition groups. The rats in the malnutrition group were provided with a low-protein diet, and daily food intake was limited to 50% for 12 weeks. Malnutrition with hypoalbuminemia decreased the body weight and induced the loss of plantaris muscle mass, but there was little change in the soleus muscle. An increase in the superoxide level in the plasma and a decrease in SOD-2 protein expression in both muscles were observed in the malnutrition group. In addition, the expression level of AMPK in the malnutrition group increased in both muscles. Conversely, the expression level of SIRT1 decreased in both muscles of the malnutrition group. In addition, malnutrition resulted in a decrease in the expression levels of PGC-1α and PINK protein, and induced a decrease in the levels of two key mitochondrial enzymes (succinate dehydrogenase and citrate synthase) and COX IV protein expression in both muscles. These results indicate that malnutrition impaired the metabolic capacity in both fast and slow muscles via AMPK-independent SIRT1 inhibition induced by increased oxidative stress.
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http://dx.doi.org/10.14814/phy2.14763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923585PMC
March 2021

Mild hyperbaric oxygen exposure attenuates rarefaction of capillary vessels in streptozotocin-induced diabetic soleus muscle in rats.

Biomed Res 2021 ;42(1):1-11

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences.

We examined the effects of mild hyperbaric oxygen (mHBO) exposure on capillary rarefaction in skeletal muscles of rats with diabetes. Streptozotocin (100 mg/kg) was administered to male Wistar rats via the tail vein to prepare a diabetic model. These rats were divided into 2 groups: the group with mHBO exposure (1.25 atmospheres absolute (ATA) with 36% oxygen; 3 h/day) and the group without mHBO exposure. Age-matched rats were used as the control group. Eight weeks later, the soleus of the rats was removed and then analyzed. With the onset of diabetes mellitus, capillary number, diameter, and volume in the soleus of the rats with diabetes decreased compared with those of the rats in the control group. In addition, increased anti-angiogenic thrombospondin-1 (TSP-1) and decreased pro-angiogenic murine double minute 2 (MDM-2) protein expressions were observed in the rats with diabetes. Alternatively, mHBO exposure attenuated the decrease in capillary diameter and volume in skeletal muscles of rats with diabetes, suppressed the overexpression of TSP-1, and restored the MDM-2 expression. These results indicate the exposure of mHBO partially attenuates capillary rarefaction in diabetic soleus muscle.
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http://dx.doi.org/10.2220/biomedres.42.1DOI Listing
January 2021

Preventive effects of low-intensity endurance exercise for severe hyperglycemia-induced capillary regression in non-obese type 2 diabetes rat skeletal muscle.

Physiol Rep 2021 Jan;9(2):e14712

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Although endurance exercise is effective for reducing diabetes-related capillary regression, it is difficult to prescribe high-intensity endurance exercise due to the potential worsening of complications in patients with severe hyperglycemia. Therefore, this study aimed to examine whether chronic low-intensity exercise training may prevent severe hyperglycemia-induced capillary regression of skeletal muscle in non-obese type 2 diabetes. Non-diabetic Sprague Dawley rats were assigned to a control (Con) group and an exercise (Ex) group. Likewise, spontaneously diabetic Torii rats were assigned to a diabetic sedentary (DM) group or a diabetic exercise (DMEx) group. Rats in the Ex and DMEx groups were placed on a motor-driven treadmill running at low speed (15 m/min) for 60 min/day, 5 days/week, for 14 weeks. Serum glucose levels were significantly increased in the DM group, but not in the DMEx group. Although the capillary-to-fiber ratio in the plantaris muscle was significantly lower in the DM group compared to the control group, the ratio in the DMEx group was significantly higher compared to the DM group. Moreover, the succinate dehydrogenase activity and expression levels of vascular endothelial growth factor and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) were reduced in the plantaris muscle of the DM group. However, those in the DMEx group were significantly higher than those in the DM group. These results indicate that low-intensity chronic endurance exercise training has the potential to prevent the progression of capillary regression in the skeletal muscles of non-obese type 2 diabetes patients with severe hyperglycemia.
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http://dx.doi.org/10.14814/phy2.14712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814498PMC
January 2021

Protective effects of low-intensity exercise on metabolic oxidative capacity and capillarization in skeletal muscle of non-obese diabetic rats.

Biomed Res 2020 ;41(5):227-236

Rehabilitation Science, Graduate School of Health Sciences, Kobe University.

Diabetes mellitus induces skeletal muscle dysfunction, such as decreased metabolic activity and capillarization. This study aimed to investigate the effects of aerobic low intensity exercise training on metabolic oxidative capacity and capillarization in skeletal muscle of non-obese diabetic rats. Eleven to twenty-five week-old male non-obese Spontaneous Diabetic Torii (SDT) rats (n = 11) and age-matched healthy male Sprague-Dawley SD rats (n = 11) were randomly assigned to either exercise or sedentary groups. The exercise training was performed on a low-speed motorized treadmill (15 m min) for 60 min per session, 5 sessions per week for 14 weeks in exercised groups. Sedentary SDT rats resulted in hyperglycemia, reduction of metabolic oxidative enzyme, and low percentage of oxidative fibers in the skeletal muscles. The low-intensity exercise training inhibited the growth-related increase in glucose level, and increased the muscle oxidative enzyme in exercised SDT rats compared with sedentary SDT rats. In addition, the exercise program prevented capillary regression in the skeletal muscle of diabetic rats. These results suggest that low-intensity exercise training may be an effective treatment to counter the detrimental effects of type 2 diabetes mellitus on the oxidative capacity and the capillary network of skeletal muscles.
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http://dx.doi.org/10.2220/biomedres.41.227DOI Listing
January 2020

Effects of reloading after chronic neuromuscular inactivity on the three-dimensional capillary architecture in rat soleus muscle.

Acta Histochem 2020 Oct 25;122(7):151617. Epub 2020 Aug 25.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe Suma-ku, Hyogo, 654-0142, Japan. Electronic address:

The purpose of the study was to investigate the effects of ambulatory reloading following hindlimb unloading on the three-dimensional (3D) capillary architecture of rat soleus muscle. In this study, 15 male Sprague-Dawley rats were used. The rats were randomly assigned to the following 3 groups: a normal weight bearing control group (CON), 14 days of hindlimb unloading group (HU), and 14 days of hindlimb unloading followed by 7 days of ambulatory reloading group (HU-RL). The capillary diameter and volume were measured using confocal laser microscopy, and capillary number was determined by two-dimensional (2D) capillary staining in the soleus muscle of each group. The capillary diameter and volume as well as the capillary number were significantly lower in the HU group than in the CON group and significantly higher in the HU-RL group than in the HU group. These results provided novel information about the effectiveness of reloading following unloading on not only the 2D increase in capillary number but also the 3D capillary remodeling in the diameter and volume within the unloaded soleus muscle.
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http://dx.doi.org/10.1016/j.acthis.2020.151617DOI Listing
October 2020

Licorice flavonoid oil supplementation promotes a reduction of visceral fat in exercised rats.

J Sports Med Phys Fitness 2021 Mar 1;61(3):480-488. Epub 2020 Oct 1.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan -

Background: The beneficial effect of exercise combined with licorice flavonoid oil supplementation on visceral fat was investigated.

Methods: Male Sprague-Dawley rats were divided into 4 groups: control, exercise (Ex), control with licorice flavonoid oil supplementation (LFO), and exercise with licorice flavonoid oil supplementation (ExLFO) groups. The rats in the Ex and ExLFO groups ran on a treadmill (20-degree incline at 20 m/min for 30 min/day) 5 times a week for 7 weeks, and those in the LFO and ExLFO groups were orally administered with licorice flavonoid oil daily using a feeding needle.

Results: Exercise or licorice flavonoid oil supplementation resulted in the reduction of the visceral fat mass and adipocyte size, respectively. In addition, exercise combined with licorice flavonoid oil supplementation more effectively decreased both measures. Exercise alone increased the β-hydroxyacyl-CoA dehydrogenase (β-HAD) and citrate synthase (CS) activities in the soleus and plantaris muscles, and licorice flavonoid oil supplementation alone increased the hepatic carnitine palmitoyl transferase-2 (CPT-2) activity. Furthermore, the combination of exercise and licorice flavonoid oil supplementation enhanced the both muscular β-HAD and CS activities, and hepatic CPT-2 activity.

Conclusions: These results suggest that exercise combined with licorice flavonoid oil supplementation may be effective to decrease visceral adipose tissue via enhancing skeletomuscular and hepatic fatty acids oxidative capacity.
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http://dx.doi.org/10.23736/S0022-4707.20.11260-XDOI Listing
March 2021

High-intensity ultrasound irradiation promotes the release of extracellular vesicles from C2C12 myotubes.

Ultrasonics 2021 Feb 5;110:106243. Epub 2020 Sep 5.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Skeletal muscle is an important secretory organ in mammals, producing myriad chemical mediators ("myokines") with distinct biological action in different tissues, including anti-inflammatory activity. Extracellular vesicles (EVs) have recently been identified as a mode of myokine transport from muscle, facilitating such anti-inflammatory activity. In this report, we have demonstrated that high-intensity ultrasound (US) strongly induces EV secretion from cultured myotubes without a reduction in cell viability. High-intensity US of 3.0 W/cm with 20% duty cycle increased the number of EVs by 2-fold compared to control at 6 h. This effect was specific to EVs in the 100-150 nm size range. Thus, high-intensity US is a novel modality for inducing myocellular EV release and may hold therapeutic value.
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http://dx.doi.org/10.1016/j.ultras.2020.106243DOI Listing
February 2021

Differential effects of pre-exercise on cancer cachexia-induced muscle atrophy in fast- and slow-twitch muscles.

FASEB J 2020 11 5;34(11):14389-14406. Epub 2020 Sep 5.

Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.

We hypothesized that pre-exercise may effectively prevent cancer cachexia-induced muscle atrophy in both fast- and slow-twitch muscle types. Additionally, the fast-twitch muscle may be more affected by cancer cachexia than slow-twitch muscle. This study aimed to evaluate the effects of pre-exercise on cancer cachexia-induced atrophy and on atrophy in fast- and slow-twitch muscles. Twelve male Wistar rats were randomly divided into sedentary and exercise groups, and another 24 rats were randomly divided into control, pre-exercise, cancer cachexia induced by intraperitoneal injections of ascites hepatoma AH130 cells, and pre-exercise plus cancer cachexia groups. We analyzed changes in muscle mass and in gene and protein expression levels of major regulators and indicators of muscle protein degradation and synthesis pathways, angiogenic factors, and mitochondrial function in both the plantaris and soleus muscles. Pre-exercise inhibited muscle mass loss, rescued protein synthesis, prevented capillary regression, and suppressed hypoxia in the plantaris and soleus muscles. Pre-exercise inhibited mitochondrial dysfunction differently in fast- and slow-twitch muscles. These results suggested that pre-exercise has the potential to inhibit cancer-cachexia-induced muscle atrophy in both fast- and slow-twitch muscles. Furthermore, the different progressions of cancer-cachexia-induced muscle atrophy in fast- and slow-twitch muscles are related to differences in mitochondrial function.
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http://dx.doi.org/10.1096/fj.202001330RDOI Listing
November 2020

Preventive effects of medium-chain triglycerides supplementation on the oxidative capacity in skeletal muscle under cachectic condition.

Biomed Res 2020 ;41(4):179-186

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences.

Cachexia is a multifactorial condition characterized by muscle mass loss and induces metabolic dysfunction of the skeletal muscles. The preventive effects of medium-chain triglycerides (MCT) supplementation on the oxidative capacity in skeletal muscle under cachectic condition were investigated in the present study. ICR mice were randomly divided into four groups; control, lipopolysaccharide (LPS), LPS plus long-chain triglycerides (LCT) and LPS plus MCT supplementation. LCT and MCT oil were administered to the LPS + LCT and LPS + MCT groups orally (5.0 g/kg body weight/day) by a catheter for one week. Cachexia was induced in the LPS, LPS + LCT, and LPS + MCT groups via LPS injection (7.5 mg/kg body weight, i.p.) after the supplementation. LPS induced a reduction of ketone bodies concentration in blood plasma. LPS also induced a decrease in succinate dehydrogenase activity and PGC-1α expression level in tibialis anterior muscles. Meanwhile, MCT supplementation suppressed a decrease in ketone bodies concentration and succinate dehydrogenase activity. In addition, MCT supplementation increased the level of citrate synthase activity in the muscles. These results suggested the preventive effect of MCT supplementation on oxidative capacity in skeletal muscle and the involvements of ketone bodies regulation under cachectic condition.
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http://dx.doi.org/10.2220/biomedres.41.179DOI Listing
January 2020

Acute effects of lactic acid-fermented and enzyme-digested soybean on protein synthesis via mTOR signaling in the skeletal muscle.

Biosci Biotechnol Biochem 2020 Nov 22;84(11):2360-2366. Epub 2020 Jul 22.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences , Kobe, Japan.

Protein-containing nutrients result in the efficient hypertrophy of muscles by increasing muscle protein synthesis. Soybean is often ingested by athletes or individuals who exercise; however, it takes very long to be absorbed. Lactic acid-fermented and enzyme-digested (LFED) soybean is absorbed faster than untreated soybean. This study aims at determining muscle protein synthesis after ingesting a single bolus of soybean or LFED soybean produced by lactic acid bacteria and protease digestion. Eight-week-old overnight-fasted ICR mice were administered powdered or LFED soybean. Mice were euthanized at 7, 15, 30, 60, 90, and 120 min after soybean intake. We have demonstrated that LFED soybean administration was quicker in stimulating muscle protein synthesis by activating mammalian target of rapamycin (mTOR) signaling than orally ingesting untreated soybean in the gastrocnemius muscle. These results suggested that LFED soybean is a more efficient source of nutrition for muscle hypertrophy than untreated soybean.
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http://dx.doi.org/10.1080/09168451.2020.1795810DOI Listing
November 2020

Protective Effects of Astaxanthin Supplementation against Ultraviolet-Induced Photoaging in Hairless Mice.

Biomedicines 2020 Jan 21;8(2). Epub 2020 Jan 21.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo 654-0142, Japan.

Ultraviolet (UV) light induces skin photoaging, which is characterized by thickening, wrinkling, pigmentation, and dryness. Astaxanthin (AST), a ketocarotenoid isolated from , has been extensively studied owing to its possible effects on skin health as well as UV protection. In addition, AST attenuates the increased generation of reactive oxygen species (ROS) and capillary regression of the skeletal muscle. In this study, we investigated whether AST could protect against UV-induced photoaging and reduce capillary regression in the skin of HR-1 hairless mice. UV light induces wrinkle formation, epidermal thickening, and capillary regression in the dermis of HR-1 hairless mice. The administration of AST reduced the UV-induced wrinkle formation and skin thickening, and increased collagen fibers in the skin. AST supplementation also inhibited the generation of ROS, decreased wrinkle formation, reduced epidermal thickening, and increased the density of capillaries in the skin. We also found an inverse correlation between wrinkle formation and the density of capillaries. An association between photoaging and capillary regression in the skin was also observed. These results suggest that AST can protect against photoaging caused by UV irradiation and the inhibitory effects of AST on photoaging may be associated with the reduction of capillary regression in the skin.
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http://dx.doi.org/10.3390/biomedicines8020018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168265PMC
January 2020

Effects of combined treatment with blood flow restriction and low-current electrical stimulation on muscle hypertrophy in rats.

J Appl Physiol (1985) 2019 11 26;127(5):1288-1296. Epub 2019 Sep 26.

Department of Rehabilitation Science, Kobe University Graduate School of Health Science, Kobe, Japan.

This study aimed to clarify the effects of a combined treatment comprising blood flow restriction and low-current electrical stimulation on skeletal muscle hypertrophy in rats. Male Wistar rats were divided into control (Cont), blood flow restriction (Bfr), electrical stimulation (Es), or Bfr with Es (Bfr + Es) groups. Pressure cuffs (80 mmHg) were placed around the thighs of Bfr and Bfr + Es rats. Low-current Es was applied to calf muscles in the Es and Bfr + Es rats. In , a 1-day treatment regimen (5-min stimulation, followed by 5-min rest) was delivered four times to study the acute effects. In , the same treatment regimen was delivered three times/wk for 8 wk. Body weight, muscle mass, changes in maximal isometric contraction, fiber cross-sectional area of the soleus muscle, expression of phosphorylated and total-ERK1/2, phosphorylated-rpS6 Ser, phosphorylated and total Akt, and phosphorylated-rpS6 Ser were measured. Bfr and Es treatment alone failed to induce muscle hypertrophy and increase the expression of phosphorylated rpS6 Ser. Combined Bfr + Es upregulated muscle mass, increased the fiber cross-sectional area, and increased phosphorylated rpS6 Ser expression and phosphorylated rpS6 Ser expression compared with controls. Combined treatment with Bfr and low-current Es can induce muscle hypertrophy via activation of two protein synthesis signaling pathways. This treatment should be introduced for older patients with sarcopenia and others with muscle weakness. We investigated the acute and chronic effect of low-current electrical stimulation with blood flow restriction on skeletal muscle hypertrophy and the mechanisms controlling the hypertrophic response. Low-current electrical stimulation could not induce skeletal muscle hypertrophy, but a combination treatment did. Blood lactate and growth hormone levels were increased in the early response. Moreover, activation of ERK1/2 and mTOR pathways were observed in both the acute and chronic response, which contribute to muscle hypertrophy.
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http://dx.doi.org/10.1152/japplphysiol.00070.2019DOI Listing
November 2019

Effects of astaxanthin supplementation and electrical stimulation on muscle atrophy and decreased oxidative capacity in soleus muscle during hindlimb unloading in rats.

J Physiol Sci 2019 Sep 4;69(5):757-767. Epub 2019 Jul 4.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe-shi, Hyogo, 654-0142, Japan.

The effects of a combination of the antioxidant astaxanthin (AX) and electrical stimulation (ES) on muscle mass and mitochondrial oxidative capacity were investigated in the soleus muscle of hindlimb unloaded rats. Five groups of male Sprague-Dawley rats were used; control, 1-week hindlimb unloading (HU), HU + AX, HU + ES, and HU + AX + ES. Respective rats in the AX groups received 50-mg/kg AX twice daily during HU. Calf muscles of rats in the ES groups were electrically stimulated for 240 s/day during HU. One-week HU decreased muscle mass along with decreased FoxO3a phosphorylation and increased ubiquitinated proteins expressions, decreased oxidative enzymatic activity accompanied with decline in PGC-1α protein expression, and increased reactive oxygen species production. However, the combination treatment could synergistically attenuate/suppress all HU-related changes, suggesting protective effects on muscle atrophy and decreased muscle oxidative capacity due to chronic neuromuscular inactivity.
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http://dx.doi.org/10.1007/s12576-019-00692-7DOI Listing
September 2019

Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.

FASEB J 2019 07 27;33(7):7852-7862. Epub 2019 Mar 27.

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

We hypothesized that low-intensity endurance exercise might be more effective in preventing cancer cachexia-induced muscle atrophy through both an increase in protein synthesis and a decrease in protein degradation. The purpose of present study was to evaluate the effects and to clarify the mechanism of low-intensity endurance exercise on cancer cachexia-induced muscle atrophy. Twenty-four male Wistar rats were randomly divided into 4 groups: control (Cont), Cont plus exercise (Ex), AH130-induced cancer cachexia (AH130), and AH130 plus Ex. Cancer cachexia was induced by intraperitoneal injections with AH130 Yoshida ascites hepatoma cells; we analyzed the changes in muscle mass and the gene and protein expression levels of major regulators or indicators of skeletal muscle protein degradation and synthesis pathway in the soleus muscles. Low-intensity exercise inhibited the muscle mass loss through a suppression of the ubiquitin-proteasome pathway, increased hypoxia-inducible factor- 1α and phosphorylated AMPK, and inhibited the deactivation of mammalian target of rapamycin pathway in the soleus muscle, which contributed to the prevention of cancer cachexia-induced muscle atrophy. These results suggest that low-intensity exercise has the potential to become an effective therapeutic intervention for the prevention of cancer cachexia-induced muscle atrophy.-Tanaka, M., Sugimoto, K., Fujimoto, T., Xie, K., Takahashi, T., Akasaka, H., Kurinami, H., Yasunobe, Y., Matsumoto, T., Fujino, H., Rakugi, H. Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.
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http://dx.doi.org/10.1096/fj.201802430RDOI Listing
July 2019

Inhibitory Effects of Short-Chain Fatty Acids and ω-3 Polyunsaturated Fatty Acids on Profibrotic Factors in Dermal Fibroblasts.

Eplasty 2019 1;19:e4. Epub 2019 Mar 1.

Division of Nutrition and Metabolism, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Dermal fibroproliferative disorders impair patients' quality of life. Although several therapeutic approaches exist for treatment of dermal scars, the development of effective ointments with few adverse effects could improve these therapeutic methods. Short-chain and ω-3 polyunsaturated fatty acids are reported to be immunomodulators with anti-inflammatory properties. Our aim was to evaluate anti-inflammatory and antifibrogenic effects of these fatty acids in human dermal fibroblasts. Cells were incubated with short-chain fatty acids (butyrate or propionate; 0-16 mM) and/or ω-3 polyunsaturated fatty acids (docosahexaenoic acid or eicosapentaenoic acid; 0-100 μM) for 24 hours to evaluate antifibrogenic effects and for 3 or 48 hours to evaluate anti-inflammatory effects after stimulation with lipopolysaccharide or without stimulation. Expression levels of α-smooth muscle actin, collagen I, collagen III, and IL-6 were evaluated, as were cell proliferation, stress fiber formation, and histone acetylation. In the lipopolysaccharide-unstimulated group, butyrate inhibited mRNA expression of α-smooth muscle actin and collagen III more effectively than propionate and increased histone acetylation. Docosahexaenoic acid inhibited mRNA expression of α-smooth muscle actin and collagen III, whereas eicosapentaenoic acid did not. Combining butyrate with docosahexaenoic acid had stronger effects, downregulating α-smooth muscle actin, collagen I, and collagen III mRNA. As for cell proliferation and stress fiber formation, butyrate acted as a stronger inhibitor than docosahexaenoic acid and the combined administration had stronger effects. In the lipopolysaccharide-stimulated group, butyrate and docosahexaenoic acid attenuated IL-6 mRNA upregulation by lipopolysaccharide. Butyrate and docosahexaenoic acid may be a novel therapeutic approach to treatment of dermal fibroproliferative disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404726PMC
March 2019

Application of transcutaneous carbon dioxide improves capillary regression of skeletal muscle in hyperglycemia.

J Physiol Sci 2019 Mar 26;69(2):317-326. Epub 2018 Nov 26.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan.

The purpose of the present study was to determine the effects of transcutaneous CO application on the blood flow and capillary architecture of the soleus muscle in rats with streptozotocin (STZ)-induced hyperglycemia. Wistar rats were randomly divided into four groups: control, control + CO-treated, STZ-induced hyperglycemia, and STZ-induced hyperglycemia + CO-treated groups. Blood flow in soleus muscle increased during the transcutaneous CO exposure, and continued to increase for 30 min after the treatment. In addition, the transcutaneous CO attenuated a decrease in capillary and the expression level of eNOS and VEGF protein, and an increase in the expression level of MDM-2 and TSP-1 protein of soleus muscle due to STZ-induced hyperglycemia. These results indicate that the application of transcutaneous CO could improve capillary regression via the change of pro- and anti-angiogenesis factors, which might be induced by an increase in blood flow.
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http://dx.doi.org/10.1007/s12576-018-0648-yDOI Listing
March 2019

Protective effects of Brazilian propolis supplementation on capillary regression in the soleus muscle of hindlimb-unloaded rats.

J Physiol Sci 2019 Mar 19;69(2):223-233. Epub 2018 Sep 19.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan.

The protective effects of Brazilian propolis on capillary regression induced by chronically neuromuscular inactivity were investigated in rat soleus muscle. Four groups of male Wistar rat were used in this study; control (CON), control plus Brazilian propolis supplementation (CON + PP), 2-week hindlimb unloading (HU), and 2-week hindlimb unloading plus Brazilian propolis supplementation (HU + PP). The rats in the CON + PP and HU + PP groups received two oral doses of 500 mg/kg Brazilian propolis daily (total daily dose 1000 mg/kg) for 2 weeks. Unloading resulted in a decrease in capillary number, luminal diameter, and capillary volume, and an increase in the expression of anti-angiogenic factors, such as p53 and TSP-1, within the soleus muscle. Brazilian propolis supplementation, however, prevented these changes in capillary structure due to unloading through the stimulation of pro-angiogenic factors and suppression of anti-angiogenic factors. These results suggest that Brazilian propolis is a potential non-drug therapeutic agent against capillary regression induced by chronic unloading.
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http://dx.doi.org/10.1007/s12576-018-0639-zDOI Listing
March 2019

Effects of combined treatment with blood flow restriction and low-intensity electrical stimulation on diabetes mellitus-associated muscle atrophy in rats.

J Diabetes 2019 Apr 30;11(4):326-334. Epub 2018 Oct 30.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Background: Diabetes mellitus (DM) results in decreased muscle mass and harmful complications. Blood flow restriction (Bfr) and electrical stimulation (ES) increase muscle protein synthesis. We hypothesized that combined Bfr and low-intensity ES may be more effective in preventing diabetes-associated muscle atrophy by inhibiting the downregulation of protein synthesis-related pathways. In this study, the effects of combined Bfr and low-intensity ES on diabetes-associated muscle atrophy were investigated by evaluating advanced glycation end-products (AGEs) and receptor for AGEs (RAGE) in rats.

Methods: Twenty-four Goto-Kakizaki (GK) rats were randomly divided into four treatment groups: sedentary DM, DM + Bfr (pressure cuffs placed around the thigh), DM + ES, and DM + Bfr + ES. Six Wistar rats were used as an age-matched control. Levels of AGEs and the expression of RAGE, extracellular signal-regulated kinase (ERK), and ribosomal protein S6 (rpS6) were determined in plantaris muscles.

Results: Diabetes resulted in a loss of muscle mass and upregulation of AGEs and RAGE in the plantaris muscle compared with the control group. Treatment with Bfr and ES alone failed to attenuate diabetes-associated loss of muscle mass, and could not prevent the upregulation of AGEs. However, the combination of Bfr and ES prevented the diabetes-associated decrease in muscle mass and upregulation of AGEs. In addition, the combination treatment prevented diabetes-associated decreases in the expression of phosphorylated rpS6.

Conclusions: Combination treatment with Bfr and ES may prevent diabetes-associated muscle atrophy by upregulating inhibition of AGEs, which leads to the activation of protein synthesis.
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http://dx.doi.org/10.1111/1753-0407.12857DOI Listing
April 2019

Remodeling of myelinated fibers and internal capillaries in distal peripheral nerves following aerobic exercise in aged rats.

J Appl Physiol (1985) 2018 10 19;125(4):1051-1061. Epub 2018 Jul 19.

Laboratory of Health and Exercise Epidemiology, Center for Health Science and Counseling, Kyushu University, Kasuga City, Fukuoka , Japan.

The aim of this study was to determine whether aerobic exercise (AE) in old age contributes to improving the morphologies of myelinated fibers (MFs) in peripheral nerves as well as capillaries. Furthermore, we investigated whether such processes are associated with complementary activity of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the circulating blood and peripheral nerve tissue. Fourteen male Wistar rats (age: 95 wk) were randomly divided into moderate AE ( n = 8) and sedentary (SED; n = 6) groups. Rats in the AE group performed treadmill running for 1 h per day for 2 wk, following which the bilateral tibial nerves of the two groups were removed to examine MF and capillary structure. Levels of BDNF and VEGF in the serum and peripheral nerves were analyzed via enzyme-linked immunosorbent assay. Myelin thickness, axon diameter, and capillary luminal diameter were significantly larger in the AE group than in the SED group ( P < 0.0001). Levels of serum BDNF and VEGF were significantly lower and higher, respectively, in the AE group than in the SED group ( P < 0.001). Conversely, BDNF and VEGF levels in tibial nerve tissue were significantly higher, respectively, and lower in the AE group than in the SED group ( P < 0.001). In conclusion, our study indicates that regular AE induces enlargement of the capillaries and thickens the myelin in aged peripheral nerves, likely via a complementary process involving BDNF and VEGF. NEW & NOTEWORTHY Accumulating evidence indicates that age-related sarcopenia is accompanied by the degeneration of myelinated fibers (MFs) in peripheral nerves. Our study indicates that regular aerobic exercise contributes to increased thickness of the myelin surrounding MFs and enlargement of the capillaries, likely via a complementary process involving brain-derived neurotrophic factor and vascular endothelial growth factor. Our findings demonstrate that regular, moderate-intensity aerobic exercise may help to prevent and reverse peripheral nerve regression in older adults.
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http://dx.doi.org/10.1152/japplphysiol.00257.2018DOI Listing
October 2018

Exercise preconditioning attenuates atrophic mediators and preserves muscle mass in acute sepsis.

Gen Physiol Biophys 2018 Jul 29;37(4):433-441. Epub 2018 Jun 29.

Department of Physical and Occupational Therapy, Faculty of Allied Health Sciences, Hashemite University, 150459, Zarqa 13115, Jordan.

Sepsis is an inflammatory condition that causes a severe and rapid loss of body proteins, especially skeletal muscles. The ubiquitin-proteasome system plays a major role in skeletal muscle proteolysis. Understanding the effects of exercise preconditioning on septic-induced ubiquitin-proteasome activation plays a pivotal role in planning rehabilitation strategies for patients who are susceptible for developing cachexia. In this study, we applied mild preconditioning exercises in the form of treadmill running for adult mice for a period of two weeks, before they were injected with lipopolysaccharide to induce sepsis. Our results show that the body weight and cross-sectional area (CSA) of muscle fibers were preserved in the pre-exercised mice. The main finding in our study was that pre-exercised mice maintained a low level of tumor necrosis factor-alpha in the gastrocnemius muscle, which resulted in a down-regulated profile of main atrophic mediators: p38, FOXO3A, and multi-ubiquitin proteins. By these findings, we conclude that a mild program of preconditioning exercises can prevent atrophy and preserve muscle mass in acute sepsis. This provides further evidence to the importance of rehabilitation planning in acute illness.
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http://dx.doi.org/10.4149/gpb_2018001DOI Listing
July 2018

Modulation of plantar pressure and gastrocnemius activity during gait using electrical stimulation of the tibialis anterior in healthy adults.

PLoS One 2018 10;13(5):e0195309. Epub 2018 May 10.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Tomogaoka, Suma-Ku, Kobe, Hyogo, Japan.

High plantar flexor moment during the stance phase is known to cause high plantar pressure under the forefoot; however, the effects on plantar pressure due to a change of gastrocnemius medialis (GM) activity during gait, have not been investigated to date. Reciprocal inhibition is one of the effects of electrical stimulation (ES), and is the automatic antagonist alpha motor neuron inhibition which is evoked by excitation of the agonist muscle. The aim of this study was to investigate the influences of ES of the tibialis anterior (TA) on plantar pressure and the GM activity during gait in healthy adults. ES was applied to the TAs of twenty healthy male adults for 30 minutes at the level of intensity that causes a full range of dorsiflexion in the ankle (frequency; 50 Hz, on-time; 10 sec, off-time; 10 sec). Subjects walked 10 meters before and after ES, and we measured the peak plantar pressure (PP), pressure time integral (PTI), and gait parameters by using an F-scan system. The percentage of integrated electromyogram (%IEMG), active time, onset time, peak time, and cessation time of TA and GM were calculated. PP and PTI under the forefoot, rear foot, and total plantar surface significantly decreased after the application of ES. Meanwhile, changes of gait parameters were not observed. %IEMG and the active time of both muscles did not change; however, onset time and peak time of GM became significantly delayed. ES application to the TA delayed the timing of onset and peak in the GM, and caused the decrease of plantar pressure during gait. The present results suggest that ES to the TA could become a new method for the control of plantar pressure via modulation of GM activity during gait.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195309PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944963PMC
July 2018

Changes in lipid metabolism and capillary density of the skeletal muscle following low-intensity exercise training in a rat model of obesity with hyperinsulinemia.

PLoS One 2018 2;13(5):e0196895. Epub 2018 May 2.

Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.

Although exercise is effective in improving obesity and hyperinsulinemia, the exact influence of exercise on the capillary density of skeletal muscles remains unknown. The aim of this study was to investigate the effects of low-intensity exercise training on metabolism in obesity with hyperinsulinemia, focusing specifically on the capillary density within the skeletal muscle. Otsuka Long-Evans Tokushima fatty (OLETF) rats were used as animal models of obesity with hyperinsulinemia, whereas Long-Evans Tokushima Otsuka (LETO) rats served as controls (no obesity, no hyperinsulinemia). The animals were randomly assigned to either non-exercise or exercise groups (treadmill running for 60 min/day, for 4 weeks). The exercise groups were further divided into subgroups according to training mode: single bout (60 min, daily) vs. multiple bout (three bouts of 20 min, daily). Fasting insulin levels were significantly higher in OLETF than in LETO rats. Among OLETF rats, there were no significant differences in fasting glucose levels between the exercise and the non-exercise groups, but the fasting insulin levels were significantly lower in the exercise group. Body weight and triacylglycerol levels in the liver were significantly higher in OLETF than in LETO rats; however, among OLETF rats, these levels were significantly lower in the exercise than in the non-exercise group. The capillary-to-fiber ratio of the soleus muscle was significantly higher in OLETF than in LETO rats; however, among OLETF rats, the ratio was lower in the exercise group than in the non-exercise group. No significant differences in any of the studied parameters were noted between the single-bout and multiple-bout exercise training modes among either OLETF or LETO rats. These results suggest that low-intensity exercise training improves insulin sensitivity and fatty liver. Additionally, the fact that attenuation of excessive capillarization in the skeletal muscle of OLETF rats was accompanied by improvement in increased body weight.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931644PMC
August 2018

Mild hyperbaric oxygen inhibits the growth-related decline in skeletal muscle oxidative capacity and prevents hyperglycemia in rats with type 2 diabetes mellitus.

J Diabetes 2018 Sep 17;10(9):753-763. Epub 2018 May 17.

Laboratory of Cell Biology and Life Science, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan.

Background: Humans and animals with type 2 diabetes mellitus (T2DM) exhibit low skeletal muscle oxidative capacity and impaired glucose metabolism. The aim of the present study was to investigate the effects of exposure to mild hyperbaric oxygen on these changes in obese rats with T2DM.

Methods: Five-week-old non-diabetic Long-Evans Tokushima Otsuka (LETO) and diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats were divided into normobaric (LETO-NB and OLETF-NB) and mild hyperbaric oxygen (LETO-MHO and OLETF-MHO) groups. The LETO-MHO and OLETF-MHO groups received 1266 hPa with 36% oxygen for 3 h daily for 22 weeks.

Results: Fasting and non-fasting blood glucose, HbA1c, and triglyceride levels were lower in the OLETF-MHO group than in the OLETF-NB group (P < 0.05). In the soleus muscle, peroxisome proliferator-activated receptor δ/β (Pparδ/β), Pparγ, and PPARγ coactivator-1α (Pgc-1α) mRNA levels were lower in the OLETF-NB group than in all other groups (P < 0.05), whereas myogenin (Myog) and myogenic factor 5 (Myf5) mRNA levels were higher in the OLETF-MHO group than in the LETO-NB and OLETF-NB groups (P < 0.05). The soleus muscles in the OLETF-NB group contained only low-oxidative Type I fibers, whereas those in all other groups contained high-oxidative Type IIA and Type IIC fibers in addition to Type I fibers.

Conclusions: Exposure to mild hyperbaric oxygen inhibits the decline in skeletal muscle oxidative capacity and prevents the hyperglycemia associated with T2DM. Pgc-1α, Myog, and Myf5 mRNA levels appear to be closely associated with skeletal muscle oxidative capacity in rats with T2DM.
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http://dx.doi.org/10.1111/1753-0407.12666DOI Listing
September 2018

Preventive effects of nucleoprotein supplementation combined with intermittent loading on capillary regression induced by hindlimb unloading in rat soleus muscle.

Physiol Rep 2017 Feb 27;5(4). Epub 2017 Feb 27.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan

Physical inactivity leads to muscle atrophy and capillary regression in the skeletal muscle. Intermittent loading during hindlimb unloading attenuates the muscle atrophy, meanwhile the capillary regression in the skeletal muscle is not suppressed. Nucleoprotein has antioxidant capacity and may prevent capillary regression. Therefore, we assessed the combined effects of intermittent loading with nucleoprotein supplementation on capillary regression induced by hindlimb unloading. Five groups of rats were assigned: control (CON), 7 days hindlimb unloading (HU), HU plus nucleoprotein supplementation (HU + NP), intermittent loading during HU (HU + IL), and intermittent loading combined with nucleoprotein supplementation during HU (HU + IL + NP). Seven days HU resulted in decrease in capillary number-to-fiber number (C/F) ratio accompanied with disuse-associated changes in fetal liver kinase-1 (Flk-1), a proangiogenesis factor, and thrombospondin-1 (TSP-1), an antiangiogenesis factor, in the soleus muscle. In addition, citrate synthase (CS) activity was decreased and protein level of superoxide dismutase (SOD)-2 was increased. Neither nucleoprotein supplementation nor intermittent loading prevented the decrease in the C/F ratio, whereas nucleoprotein supplementation combined with intermittent loading prevented the regression of capillary during unloading. Moreover, the levels of Flk-1, TSP-1, and SOD-2 protein and the CS activity were maintained up to control levels. These results suggested that nucleoprotein supplementation combined with intermittent loading was effective to prevent capillary regression induced by muscle atrophy.
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http://dx.doi.org/10.14814/phy2.13134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328772PMC
February 2017

Low-Intensity Ultrasound Enhances Histone Acetylation and Inhibition of Interleukin 6 Messenger RNA Expression by the Histone Deacetylase Inhibitor Sodium Butyrate in Fibroblasts.

J Ultrasound Med 2017 May 3;36(5):879-885. Epub 2017 Feb 3.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Objectives: Sodium butyrate, an inhibitor of histone deacetylase, has several therapeutic actions, including anti-inflammation. These actions depend on the concentration of sodium butyrate. In addition, lower concentrations have shown no effect on inflammation. Sonoporation by ultrasound can modify the permeability of the cell plasma membrane. Thus, the effects of sodium butyrate may be enhanced by the ultrasonic acoustics. Therefore, the facilitative effects of low-intensity ultrasound on histone acetylation and interleukin 6 (IL-6) regulation by sodium butyrate were investigated in this study.

Methods: Human dermal fibroblasts were treated with 1-mM sodium butyrate for 3 hours with 20 minutes of 0.1-W/cm pulsed or continuous ultrasound irradiation at the beginning of the sodium butyrate treatments.

Results: The combination of treatments with sodium butyrate and ultrasound significantly increased histone acetylation in fibroblasts (P < .05), whereas sodium butyrate could not increase histone acetylation. In addition, this combined treatment significantly suppressed the IL-6 messenger RNA expression level with lipopolysaccharide stimulation for 1 hour (P < .05). Meanwhile, the treatment with sodium butyrate alone could not suppress IL-6 messenger RNA expression in fibroblasts. These effects were achieved with both 20% pulsed and continuous ultrasound but not observed with ultrasound treatment alone.

Conclusions: These results suggest that low-intensity ultrasound treatment promotes the physiologic actions of sodium butyrate as a histone deacetylase inhibitor.
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http://dx.doi.org/10.7863/ultra.16.04020DOI Listing
May 2017

Enterococcus faecium strain R30 increases red blood cell velocity and prevents capillary regression in the soleus of hindlimb-unloaded rats via the eNOS/VEGF pathway.

Microcirculation 2017 05;24(4)

Department of Rehabilitation Science, Graduate School of Health Sciences, Kobe University, Kobe, Japan.

Objective: A chronic decrease in neuromuscular activity results in atrophy and capillary regression in skeletal muscles. The purposes of this study were to determine the effects of Enterococcus faecium strain R30 (R30) administration on (i) the hemodynamics of the rat soleus muscle, and (ii) the capillary regression normally associated with HU.

Methods: Experiment 1: The V was measured for up to 1 hour after administration of R30 with or without the β-blocker propranolol. Experiment 2: R30 was administered daily to control and HU rats for 2 weeks. Mean capillary luminal diameter, volume, and the levels of eNOS and VEGF protein were measured.

Results: Experiment 1: V was faster 20, 40, and 60 minutes after than before the administration of R30: This effect was suppressed by propranolol administration. Experiment 2: R30 administration during HU increased capillary luminal diameter and volume and eNOS and VEGF protein levels in the soleus of HU rats.

Conclusions: The results suggest that R30 increases V in the soleus muscle via muscle sympathetic nerve activity (Experiment 1) and that R30 supplementation lessens the capillary regression normally associated with HU via the eNOS/VEGF pathway (Experiment 2).
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http://dx.doi.org/10.1111/micc.12356DOI Listing
May 2017

Nucleoprotein supplementation enhances the recovery of rat soleus mass with reloading after hindlimb unloading-induced atrophy via myonuclei accretion and increased protein synthesis.

Nutr Res 2016 Dec 23;36(12):1335-1344. Epub 2016 Oct 23.

Rehabilitation Science, Graduate School of Health Sciences, Kobe University, 7-10-2 Tomogaoka, Kobe 654-0142, Japan. Electronic address:

Hindlimb unloading results in muscle atrophy and a period of reloading has been shown to partially recover the lost muscle mass. Two of the mechanisms involved in this recovery of muscle mass are the activation of protein synthesis pathways and an increase in myonuclei number. The additional myonuclei are provided by satellite cells that are activated by the mechanical stress associated with the reloading of the muscles and eventually incorporated into the muscle fibers. Amino acid supplementation with exercise also can increase skeletal muscle mass through enhancement of protein synthesis and nucleotide supplements can promote cell cycle activity. Therefore, we hypothesized that nucleoprotein supplementation, a combination of amino acids and nucleotides, would enhance the recovery of muscle mass to a greater extent than reloading alone after a period of unloading. Adult rats were assigned to 4 groups: control, hindlimb unloaded (HU; 14 days), reloaded (5 days) after hindlimb unloading (HUR), and reloaded after hindlimb unloading with nucleoprotein supplementation (HUR + NP). Compared with the HUR group, the HUR + NP group had larger soleus muscles and fiber cross-sectional areas, higher levels of phosphorylated rpS6, and higher numbers of myonuclei and myogenin-positive cells. These results suggest that nucleoprotein supplementation has a synergistic effect with reloading in recovering skeletal muscle properties after a period of unloading via rpS6 activation and satellite cell differentiation and incorporation into the muscle fibers. Therefore, this supplement may be an effective therapeutic regimen to include in rehabilitative strategies for a variety of muscle wasting conditions such as aging, cancer cachexia, muscular dystrophy, bed rest, and cast immobilization.
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http://dx.doi.org/10.1016/j.nutres.2016.10.007DOI Listing
December 2016

L-arginine supplementation attenuates capillary regression without increasing integrated succinate dehydrogenase activity and VEGF expression in skeletal muscle during hindlimb unloading.

Gen Physiol Biophys 2016 Oct 22;35(4):425-432. Epub 2016 Jul 22.

Department of Rehabilitation Science, Kobe University, Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan.

Decreased capillary number is observed in atrophied muscle. The change in capillary number is regulated by angiogenic factors. L-arginine enhances expression of endothelial nitric oxide synthase (eNOS), angiogenic factor, in skeletal muscle. Therefore, the aim of this study was to evaluate the effects of L-arginine supplementation on capillary regression during hindlimb unloading. Twenty-four male Wistar rats were divided into four treatment groups: (1) control, (2) L-arginine supplementation, (3) hindlimb unloading, and (4) hindlimb unloading with L-arginine supplementation. Hindlimb unloading resulted in a decrease of capillary-to-muscle fibre (C/F) ratio, eNOS expression, and integrated succinate dehydrogenase (SDH) activity. L-arginine supplementation attenuated the decrease in both eNOS expression and C/F ratio, although it did not increase integrated SDH activity in skeletal muscle. These results indicate that L-arginine supplementation is effective for maintaining capillary number in atrophied muscle, and that elevation of eNOS expression may be one mechanism associated with these responses.
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http://dx.doi.org/10.4149/gpb_2016016DOI Listing
October 2016

Astaxanthin supplementation attenuates immobilization-induced skeletal muscle fibrosis via suppression of oxidative stress.

J Physiol Sci 2017 Sep 6;67(5):603-611. Epub 2016 Oct 6.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe-shi, Hyogo, 654-0142, Japan.

Immobilization induces skeletal muscle fibrosis characterized by increasing collagen synthesis in the perimysium and endomysium. Transforming growth factor-β1 (TGF-β1) is associated with this lesion via promoting differentiation of fibroblasts into myofibroblasts. In addition, reactive oxygen species (ROS) are shown to mediate TGF-β1-induced fibrosis in tissues. These reports suggest the importance of ROS reduction for attenuating skeletal muscle fibrosis. Astaxanthin, a powerful antioxidant, has been shown to reduce ROS production in disused muscle. Therefore, we investigated the effects of astaxanthin supplementation on muscle fibrosis under immobilization. In the present study, immobilization increased the collagen fiber area, the expression levels of TGF-β1, α-smooth muscle actin, and superoxide dismutase-1 protein and ROS production. However, these changes induced by immobilization were attenuated by astaxanthin supplementation. These results indicate the effectiveness of astaxanthin supplementation on skeletal muscle fibrosis induced by ankle joint immobilization.
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http://dx.doi.org/10.1007/s12576-016-0492-xDOI Listing
September 2017