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1.
J Gerontol A Biol Sci Med Sci ; 78(4): 587-595, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-36634126

RESUMO

The purpose of this study was to investigate whether aging alters the effect of nutritional status on contraction-induced muscle protein metabolism. In an overnight fasted or fed states, the right gastrocnemius muscle of young (3 months) and aged (24 months) male C57BL/6J mice was isometrically contracted via percutaneous electrical stimulation. The left gastrocnemius muscle served as a control. In the fasted state, there were no differences in basal or contraction-induced muscle protein synthesis between young and old mice. However, in the fed state, basal muscle protein synthesis was greater in young mice, and contraction increased muscle protein synthesis only in young mice. In the fed state, although phosphorylation of 4E-BP1 was similarly increased by contraction in both ages, the increase in phosphorylation of p70S6K was greater in young mice. Our results indicate that aging impairs the ability to integrate signals from muscle contraction and nutrition, leading to aging-induced anabolic resistance to muscle contraction in the postprandial state.


Assuntos
Transdução de Sinais , Serina-Treonina Quinases TOR , Camundongos , Masculino , Animais , Serina-Treonina Quinases TOR/metabolismo , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Contração Muscular/fisiologia , Fosforilação , Envelhecimento/metabolismo , Proteínas Musculares/metabolismo
2.
Biochem Biophys Rep ; 32: 101378, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36386439

RESUMO

Duchenne muscular dystrophy (DMD) is a myopathy characterized by progressive muscle weakness caused by a mutation in the dystrophin gene on the X chromosome. We recently showed that a medium-chain triglyceride-containing ketogenic diet (MCTKD) improves skeletal muscle myopathy in a CRISPR/Cas9 gene-edited rat model of DMD. We examined the effects of the MCTKD on transcription profiles in skeletal muscles of the model rats to assess the underlying mechanism of the MCTKD-induced improvement in DMD. DMD rats were fed MCTKD or normal diet (ND) from weaning to 9 months, and wild-type rats were fed with the ND, then tibialis anterior muscles were sampled for mRNA-seq analysis. Pearson correlation heatmaps revealed a one-node transition in the expression profile between DMD and wild-type rats. A total of 10,440, 11,555 and 11,348 genes were expressed in the skeletal muscles of wild-type and ND-fed DMD rats the MCTKD-fed DMD rats, respectively. The MCTKD reduced the number of DMD-specific mRNAs from 1624 to 1350 and increased the number of mRNAs in common with wild-type rats from 9931 to 9998. Among 2660 genes were differentially expressed in response to MCTKD intake, the mRNA expression of 1411 and 1249 of them was respectively increased and decreased. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that the MCTKD significantly suppressed the mRNA expression of genes associated with extracellular matrix organization and inflammation. This suggestion was consistent with our previous findings that the MCTKD significantly suppressed fibrosis and inflammation in DMD rats. In contrast, the MCTKD significantly increased the mRNA expression of genes associated with oxidative phosphorylation and ATP production pathways, suggesting altered energy metabolism. The decreased and increased mRNA expression of Sln and Atp2a1 respectively suggested that Sarco/endoplasmic reticulum Ca2+-ATPase activation is involved in the MCTKD-induced improvement of skeletal muscle myopathy in DMD rats. This is the first report to examine transcription profiles in the skeletal muscle of CRISPR/Cas9 gene-edited DMD model rats and the effect of MCTKD feeding on it.

3.
Am J Physiol Cell Physiol ; 322(2): C275-C282, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35020502

RESUMO

Angiogenesis and muscle satellite cell (SC)-mediated myonuclear accretion are considered essential for the robust response of contraction-induced muscle hypertrophy. Moreover, both myonucleus and SCs are physically adjacent to capillaries and are the major sites for the expression of proangiogenic factors, such as VEGF, in the skeletal muscle. Thus, events involving the addition of new myonuclei via activation of SCs may play an important role in angiogenesis during muscle hypertrophy. However, the relevance among myonuclei number, capillary supply, and angiogenesis factor is not demonstrated. The Notch effector HeyL is specifically expressed in SCs in the skeletal muscle and is crucial for SC proliferation by inhibiting MyoD in overload-induced muscle hypertrophy. Here, we tested whether the addition of new myonuclei by SC in overloaded muscle is associated with angiogenic adaptation by reanalyzing skeletal muscle from HeyL-knockout (KO) mice, which show blunted responses of SC proliferation, myonucleus addition, and overload-induced muscle hypertrophy. Reanalysis confirmed blunted SC proliferation and myonuclear accretion in the plantaris muscle of HeyL-KO mice 9 wk after synergist ablation. Interestingly, the increase in capillary-to-fiber ratio observed in wild-type (WT) mice was impaired in HeyL-KO mice. In both WT and HeyL-KO mice, the expression of VEGFA and VEGFB was similarly increased in response to overload. In addition, the expression pattern of TSP-1, a negative regulator of angiogenesis, was also not changed between WT and HeyL-KO mice. Collectively, these results suggest that SCs activation-myonuclear accretion plays a crucial role in angiogenesis during overload-induced muscle hypertrophy via independent of angiogenesis regulators.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Capilares/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Neovascularização Fisiológica , Células Satélites de Músculo Esquelético/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Genótipo , Hipertrofia , Camundongos Knockout , Contração Muscular , Músculo Esquelético/patologia , Fenótipo , Células Satélites de Músculo Esquelético/patologia , Transdução de Sinais
4.
Am J Physiol Endocrinol Metab ; 321(4): E551-E559, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34423683

RESUMO

High-intensity muscle contractions (HiMCs) are known to increase c-Myc expression that is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, although c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this connection has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 wk increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-sequencing (RNA-seq) analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.NEW & NOTEWORTHY Resistance exercise is known to increase c-Myc expression, which is known to stimulate ribosome biogenesis and protein synthesis in a variety of cells. However, whether the increase in c-Myc stimulates ribosome biogenesis and protein synthesis in skeletal muscles remains unknown. We found that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1.


Assuntos
Regulação da Expressão Gênica , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Músculo Esquelético/metabolismo , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ribossomos/metabolismo , Animais , Feminino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-myc/genética , Transcriptoma
5.
Nutrition ; 91-92: 111389, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34303956

RESUMO

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.


Assuntos
Deficiências de Ferro , Treinamento Resistido , Animais , Humanos , Ferro/metabolismo , Masculino , Músculo Esquelético/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley
6.
J Appl Physiol (1985) ; 131(2): 442-453, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34138646

RESUMO

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.NEW & NOTEWORTHY 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.


Assuntos
Resistência à Insulina , Treinamento Resistido , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Masculino , Fibras Musculares Esqueléticas , Músculo Esquelético , Ratos , Ratos Sprague-Dawley
7.
J Exp Biol ; 224(10)2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-34003264

RESUMO

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.


Assuntos
Fibras Musculares Esqueléticas , Músculo Esquelético , Animais , Núcleo Celular/metabolismo , Contração Muscular , Músculo Esquelético/metabolismo , Biossíntese de Proteínas , Ratos
8.
Metabolism ; 114: 154419, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161019

RESUMO

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.


Assuntos
Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Adenilato Quinase/metabolismo , Animais , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
9.
J Physiol ; 598(23): 5453-5466, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32893874

RESUMO

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.


Assuntos
Contração Muscular , Sirolimo , Animais , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Proteínas Musculares/genética , Proteína Companheira de mTOR Insensível à Rapamicina , Sirolimo/farmacologia
10.
Nutrition ; 78: 110795, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32480256

RESUMO

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.


Assuntos
Dieta Rica em Proteínas , Treinamento Resistido , Animais , Proteínas Alimentares , Humanos , Masculino , Proteínas Musculares , Músculo Esquelético , Ratos , Ratos Sprague-Dawley
11.
Front Physiol ; 11: 469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528306

RESUMO

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.

12.
J Appl Physiol (1985) ; 128(4): 830-837, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078465

RESUMO

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.NEW & NOTEWORTHY 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.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Musculares , Proteínas Proto-Oncogênicas c-akt , Animais , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
13.
J Int Soc Sports Nutr ; 16(1): 60, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829236

RESUMO

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.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Músculo Esquelético/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Extratos Vegetais/farmacologia , Transdução de Sinais , Triterpenos/farmacologia , Animais , Dieta , Masculino , Músculo Esquelético/fisiologia , Photinia/química , Biossíntese de Proteínas , Ratos Sprague-Dawley , Ácido Ursólico
14.
Physiol Rep ; 7(21): e14270, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31691510

RESUMO

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.


Assuntos
Jejum/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal/fisiologia , Aminoácidos/metabolismo , Animais , Autofagia/fisiologia , Glicemia/metabolismo , Masculino , Biossíntese de Proteínas , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
15.
Exp Physiol ; 104(10): 1518-1531, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31328833

RESUMO

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 p70S6KThr389 and 4E-BP1Thr37/46 ) 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.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Treinamento Resistido , Adaptação Fisiológica , Tecido Adiposo/crescimento & desenvolvimento , Animais , Núcleo Celular/patologia , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fibras Musculares Esqueléticas , Atrofia Muscular/etiologia , Tamanho do Órgão , Fosforilação , Ratos , Ratos Endogâmicos OLETF
16.
Front Physiol ; 10: 406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057416

RESUMO

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.

17.
Physiol Rep ; 7(6): e14046, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30916457

RESUMO

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.


Assuntos
Densidade Óssea , Remodelação Óssea , Diabetes Mellitus Tipo 2/terapia , Treinamento Resistido , Tíbia/fisiopatologia , Animais , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Terapia por Estimulação Elétrica , Masculino , Ratos Endogâmicos OLETF , Ratos Long-Evans , Tíbia/diagnóstico por imagem , Fatores de Tempo
18.
Cell Signal ; 53: 224-233, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352253

RESUMO

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.


Assuntos
Toxinas Botulínicas/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Hexoquinase/metabolismo , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Toxinas Botulínicas/administração & dosagem , Denervação/métodos , Regulação para Baixo/efeitos dos fármacos , Feminino , Transportador de Glucose Tipo 4/genética , Hexoquinase/genética , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Regulação para Cima/efeitos dos fármacos
19.
Am J Physiol Endocrinol Metab ; 314(6): E564-E571, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29406784

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insulina/metabolismo , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/genética , Treinamento Resistido , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Regulação para Baixo/genética , Insulina/farmacologia , Resistência à Insulina/genética , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Condicionamento Físico Animal/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Endogâmicos OLETF , Ratos Long-Evans , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
20.
Physiol Rep ; 5(15)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28778992

RESUMO

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.


Assuntos
Contração Muscular , Músculo Esquelético/metabolismo , Proteólise , Transdução de Sinais , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
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