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1.
Biol Pharm Bull ; 42(9): 1437-1445, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474705

RESUMO

Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages.


Assuntos
Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/complicações , Sarcopenia/etiologia , Citocinas/imunologia , Humanos , Indicã/biossíntese , Músculo Esquelético/imunologia , Miostatina/biossíntese , Estresse Oxidativo/imunologia , Proteólise , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Sarcopenia/imunologia , Sarcopenia/metabolismo
2.
PLoS One ; 13(10): e0205664, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30379863

RESUMO

Thoroughbred horses are finely-tuned athletes with a high aerobic capacity relative to skeletal muscle mass, attributable to centuries of genetic selection for speed and stamina. Polymorphisms in the myostatin gene (MSTN), a pronounced inhibitor of skeletal muscle growth, have been shown to almost singularly account for gene-based race distance aptitude in racehorses. In Thoroughbreds, two MSTN polymorphisms, a single nucleotide variation in the first intron (SNP g.66493737C>T) and a non-coding transposable element within the promoter region (a 227 bp SINE insertion) are of particular interest. Until now, it has not been clear which of these variants affect skeletal muscle phenotypes or whether both can impact racing performance. In a large cohort of Thoroughbreds, we observed a complete concordance between the SNP and the SINE insertion. By means of in vitro assays in C2C12 myoblasts, we isolated the SNP variant from the SINE polymorphism and showed the latter is exclusively responsible for adversely affecting transcription initiation and gene expression thereby limiting myostatin protein production. Mapping the MSTN transcription start site in horse skeletal muscle likewise revealed anomalous transcription initiation in the presence of the SINE insertion. Our data provides mechanistic evidence that the SINE insertion uniquely accounts for the MSTN "speed gene" effect on race distance aptitude in the Thoroughbred horse.


Assuntos
Cavalos/genética , Íntrons , Mutagênese Insercional , Miostatina/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Seleção Artificial , Animais , Linhagem Celular , Cavalos/metabolismo , Músculo Esquelético/metabolismo , Miostatina/biossíntese , Fenótipo
3.
Biochem Biophys Res Commun ; 503(3): 1409-1414, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30025893

RESUMO

Muscle atrophy in metabolic conditions like chronic kidney disease (CKD) and diabetes are associated with glucocorticoid production, dysfunctional insulin/Akt/FoxO3 signaling and increased myostatin expression. We recently found that CREB, a transcription factor proposed to regulate myostatin expression, is highly phosphorylated in some wasting conditions. Based on a novel Akt-PDE3/4 signaling paradigm, we hypothesized that reduced Akt signaling contributes to CREB activation and myostatin expression. C2C12 myotubes were incubated with dexamethasone (Dex), an atrophy-inducing synthetic glucocorticoid. Akt/CREB signaling and myostatin expression were evaluated by immunoblot and qPCR analyses. Inhibitors of Akt, phosphodiesterase (PDE)-3/4, and protein kinase A (PKA) signaling were used to test our hypothesis. Incubating myotubes with Dex for 3-24 h inhibited Akt phosphorylation and enhanced CREB phosphorylation as well as myostatin mRNA and protein. Inhibition of PI3K/Akt signaling with LY294002 similarly increased CREB phosphorylation. Isobutyl-methylxanthine (IBMX, a pan PDE inhibitor), milrinone (PDE3 inhibitor) and rolipram (PDE4 inhibitor) augmented CREB phosphorylation and myostatin expression. Inhibition of protein kinase A by PKI reverted Dex- or IBMX-induced CREB phosphorylation and myostatin expression. Our study provides evidence supporting a newly identified mechanism by which a glucocorticoid-related reduction in Akt signaling contributes to myostatin expression via CREB activation.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Glucocorticoides/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miostatina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Miostatina/biossíntese , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Sci Rep ; 7(1): 11877, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28928419

RESUMO

Muscle wasting, also known as cachexia, is associated with many chronic diseases, which worsens prognosis of primary illness leading to enhanced mortality. Molecular basis of this metabolic syndrome is not yet completely understood. SIRT6 is a chromatin-bound member of the sirtuin family, implicated in regulating many cellular processes, ranging from metabolism, DNA repair to aging. SIRT6 knockout (SIRT6-KO) mice display loss of muscle, fat and bone density, typical characteristics of cachexia. Here we report that SIRT6 depletion in cardiac as well as skeletal muscle cells promotes myostatin (Mstn) expression. We also observed upregulation of other factors implicated in muscle atrophy, such as angiotensin-II, activin and Acvr2b, in SIRT6 depleted cells. SIRT6-KO mice showed degenerated skeletal muscle phenotype with significant fibrosis, an effect consistent with increased levels of Mstn. Additionally, we observed that in an in vivo model of cancer cachexia, Mstn expression coupled with downregulation of SIRT6. Furthermore, SIRT6 overexpression downregulated the cytokine (TNFα-IFNγ)-induced Mstn expression in C2C12 cells, and promoted myogenesis. From the ChIP assay, we found that SIRT6 controls Mstn expression by attenuating NF-κB binding to the Mstn promoter. Together, these data suggest a novel role for SIRT6 in maintaining muscle mass by controlling expression of atrophic factors like Mstn and activin.


Assuntos
Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Miocárdio/metabolismo , Miostatina/biossíntese , Sirtuínas/metabolismo , Regulação para Cima , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Ativinas/genética , Ativinas/metabolismo , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Humanos , Camundongos , Camundongos Knockout , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Miostatina/genética , NF-kappa B/genética , Ratos , Elementos de Resposta , Sirtuínas/genética
5.
Int J Cardiol ; 238: 37-42, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28465115

RESUMO

BACKGROUND: Myostatin, a negative regulator of skeletal muscle mass, is up-regulated in the myocardium of heart failure (HF) and increased myostatin is associated with weight loss in animal models with HF. Although there are disparities in pathophysiology and epidemiology between male and female patients with HF, it remains unclear whether there is gender difference in myostatin expression and whether it is associated with weight loss in HF patients. METHODS: Heart tissue samples were collected from patients with advanced heart failure (n=31, female n=5) as well as healthy control donors (n=14, female n=6). Expression levels of myostatin and its related proteins in the heart were evaluated by western blotting analysis. RESULTS: Body mass index was significantly lower in female HF patients than in male counterparts (20.0±4.2 in female vs 25.2±3.8 in male, p=0.04). In female HF patients, both mature myostatin and pSmad2 were significantly up-regulated by 1.9 fold (p=0.05) and 2.5 fold (p<0.01) respectively compared to female donors, while expression of pSmad2 was increased by 2.8 times in male HF patients compared to male healthy subjects, but that of myostatin was not. There was no significant difference in protein expression related to myostatin signaling between male and female patients. CONCLUSION: In this study, myostatin and pSmad2 were significantly up-regulated in the failing heart of female patients, but not male patients, and female patients displayed lower body mass index. Enhanced myostatin signaling in female failing heart may causally contribute to pathogenesis of HF and cardiac cachexia.


Assuntos
Insuficiência Cardíaca/metabolismo , Miostatina/biossíntese , Transdução de Sinais/fisiologia , Proteína Smad2/biossíntese , Regulação para Cima/fisiologia , Adulto , Idoso , Feminino , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade
6.
Medicine (Baltimore) ; 96(16): e6579, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28422851

RESUMO

Patients with coronary heart disease or acute myocardial infarction after cardiac catheterization with stenting referred for phase II cardiac rehabilitation (CR) were grouped according to their preference. Cardio-pulmonary exercise testing (CPET) was used to determine oxygen uptake ((Equation is included in full-text article.)) at peak exercise and anaerobic threshold (AT). The control patients received counseling only while the experiment group received 36 sessions of CR in 3 to 6 months. Exercise physiology parameters and serum myokines (myostatin, insulin-like growth factor-1 (IGF-1), and interleukin-6 (IL-6) were measured pre- and postrehabilitation.There were 29 patients in the experiment group and 10 in the control group, with no significant differences in baseline parameters. The experiment group had prominent progress in aerobic capacity and body composition after CR, but their serum myokine concentrations did not change significantly. Serum myostatin is positively correlated to peak (Equation is included in full-text article.)pre- and post-training, and pretraining AT (Equation is included in full-text article.), after adjusting for age, sex, and body composition. Serum IGF-1 is positively correlated with grip strength before training.Serum myostatin level is positively correlated to aerobic capacity, and IGF-1 level is positively correlated to grip strength in cardiac patients receiving CR.


Assuntos
Reabilitação Cardíaca/métodos , Teste de Esforço , Fator de Crescimento Insulin-Like I/biossíntese , Interleucina-6/biossíntese , Miostatina/biossíntese , Idoso , Cateterismo Cardíaco , Doença das Coronárias/reabilitação , Doença das Coronárias/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Infarto do Miocárdio/reabilitação , Infarto do Miocárdio/cirurgia , Consumo de Oxigênio , Estudos Prospectivos , Stents
7.
Int J Med Sci ; 13(9): 680-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27647997

RESUMO

Effects of myostatin (MSTN)-suppression on the regeneration of injured skeletal muscle under unloading condition were investigated by using transgenic mice expressing a dominant-negative form of MSTN (MSTN-DN). Both MSTN-DN and wild-type (WT) mice were subjected to continuous hindlimb suspension (HS) for 6 weeks. Cardiotoxin (CTX) was injected into left soleus muscle under anesthesia 2 weeks after the initiation of HS. Then, the soleus muscles were excised following 6-week HS (4 weeks after CTX-injection). CTX-injection caused to reduce the soleus fiber cross-sectional area (CSA) in WT mice under both unloading and weight-bearing conditions, but not in MSTN-DN mice. Under unloading condition, CTX-injected muscle weight and fiber CSA in MSTN-DN mice were significantly higher than those in WT mice. CTX-injected muscle had many damaged and regenerating fibers having central nuclei in both WT and MSTN-DN mice. Significant increase in the population of Pax7-positive nuclei in CTX-injected muscle was observed in MSTN-DN mice, but not in WT mice. Evidences indicate that the suppression of MSTN cause to increase the regenerative potential of injured soleus muscle via the increase in the population of muscle satellite cells regardless of unloading conditions.


Assuntos
Membro Posterior/crescimento & desenvolvimento , Músculo Esquelético/crescimento & desenvolvimento , Miostatina/biossíntese , Regeneração , Animais , Cardiotoxinas/administração & dosagem , Membro Posterior/efeitos dos fármacos , Membro Posterior/lesões , Membro Posterior/fisiopatologia , Humanos , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Músculo Esquelético/fisiopatologia , Miostatina/antagonistas & inibidores , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/patologia , Suporte de Carga
8.
Sci Rep ; 6: 32084, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27549031

RESUMO

Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease (CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate (IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-ß1) in C2C12 cells. IS also enhanced the production of muscle atrophy-related genes, myostatin and atrogin-1. These effects induced by IS were suppressed in the presence of an antioxidant or inhibitors of the organic anion transporter and aryl hydrocarbon receptor. The administered IS was distributed to skeletal muscle and induced superoxide production in half-nephrectomized (1/2 Nx) mice. The chronic administration of IS significantly reduced the body weights accompanied by skeletal muscle weight loss. Similar to the in vitro data, IS induced the expression of myostatin and atrogin-1 in addition to increasing the production of inflammatory cytokines by enhancing oxidative stress in skeletal muscle. These data suggest that IS has the potential to accelerate skeletal muscle atrophy by inducing oxidative stress-mediated myostatin and atrogin-1 expression.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Indicã/toxicidade , Proteínas Musculares/biossíntese , Músculo Esquelético/efeitos dos fármacos , Miostatina/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Proteínas Ligases SKP Culina F-Box/biossíntese , Sarcopenia/induzido quimicamente , Animais , Antioxidantes/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Proteínas Musculares/genética , Músculo Esquelético/patologia , Mioblastos/efeitos dos fármacos , Miostatina/genética , Nefrectomia , Tamanho do Órgão/efeitos dos fármacos , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Proteínas Ligases SKP Culina F-Box/genética , Sarcopenia/genética , Sarcopenia/metabolismo , Superóxidos/metabolismo , Uremia/metabolismo , Uremia/patologia , Perda de Peso/efeitos dos fármacos
9.
Int J Cardiol ; 215: 384-7, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27128567

RESUMO

BACKGROUND: Myostatin has been shown to regulate skeletal and cardiac muscle growth. However, its status on long-term hypertrophied myocardium has not been addressed. The purpose of this study was to evaluate the expression of myocardial myostatin and its antagonist follistatin in spontaneously hypertensive rats (SHR) with heart failure. METHODS: Eighteen-month-old SHR were evaluated to identify clinical features of heart failure such as tachypnea/labored respiration and weight loss. After heart failure was detected, rats were subjected to echocardiogram and euthanized. Age-matched normotensive Wistar-Kyoto (WKY) rats were used as controls. Myostatin and follistatin protein expression was assessed by Western blotting. Statistical analysis was performed by Student's t test. RESULTS: All SHR (n=8) presented right ventricular hypertrophy and five had lung congestion. SHR had left chambers hypertrophy and dilation (left atrial diameter: WKY 5.73±0.59; SHR 7.28±1.17mm; p=0.004; left ventricular (LV) diastolic diameter/body weight ratio: WKY 19.6±3.1; SHR 27.7±4.7mm/kg; p=0.001), and LV systolic dysfunction (midwall fractional shortening: WKY 34.9±3.31; SHR 24.8±3.20%; p=0.003). Myocyte diameter (WKY 23.1±1.50, SHR 25.5±1.33µm; p=0.004) and myocardial interstitial collagen fraction (WKY 4.86±0.01; SHR 8.36±0.02%; p<0.001) were increased in the SHR. Myostatin (WKY 1.00±0.16; SHR 0.77±0.23 arbitrary units; p=0.035) and follistatin (WKY 1.00±0.35; SHR 0.49±0.18 arbitrary units; p=0.002) expression was lower in SHR. Myostatin and follistatin expression negatively correlated with LV diastolic diameter-to-body weight ratio and LV systolic diameter, and positively correlated with midwall fractional shortening. CONCLUSION: Myostatin and follistatin protein expression is reduced in the long-term hypertrophied myocardium from spontaneously hypertensive rats with heart failure.


Assuntos
Insuficiência Cardíaca/metabolismo , Hipertensão/metabolismo , Miocárdio/metabolismo , Miostatina/biossíntese , Animais , Peso Corporal , Ecocardiografia , Folistatina/biossíntese , Folistatina/metabolismo , Insuficiência Cardíaca/diagnóstico por imagem , Masculino , Miocárdio/patologia , Miostatina/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/metabolismo
10.
Calcif Tissue Int ; 97(6): 602-10, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26340892

RESUMO

Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.


Assuntos
Força da Mão , Fibras Musculares Esqueléticas/patologia , Miostatina/biossíntese , Receptores de Calcitriol/deficiência , Deficiência de Vitamina D/fisiopatologia , Animais , Modelos Animais de Doenças , Força da Mão/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Deficiência de Vitamina D/metabolismo
11.
IUBMB Life ; 67(8): 589-600, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26305594

RESUMO

Myostatin is a secreted growth and differentiation factor that belongs to the TGF-ß superfamily. Myostatin is predominantly synthesized and expressed in skeletal muscle and thus exerts a huge impact on muscle growth and function. In keeping with its negative role in myogenesis, myostatin expression is tightly regulated at several levels including epigenetic, transcriptional, post-transcriptional, and post-translational. New revelations regarding myostatin regulation also offer mechanisms that could be exploited for developing myostatin antagonists. Increasingly, it is becoming clearer that besides its conventional role in muscle, myostatin plays a critical role in metabolism. Hence, molecular mechanisms by which myostatin regulates several key metabolic processes need to be further explored.


Assuntos
Diferenciação Celular/genética , Desenvolvimento Muscular/genética , Miostatina/genética , Fator de Crescimento Transformador beta/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Miostatina/biossíntese , Miostatina/metabolismo , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional
12.
Int J Mol Med ; 36(1): 29-42, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25955031

RESUMO

In the present study, we aimed to determine whether ethanol extracts of Fructus Schisandrae (FS), the dried fruit of Schizandra chinensis Baillon, mitigates the development of dexamethasone-induced muscle atrophy. Adult SPF/VAT outbred CrljOri:CD1 (ICR) mice were either treated with dexamethasone to induce muscle atrophy. Some mice were treated with various concentrations of FS or oxymetholone, a 17α-alkylated anabolic-androgenic steroid. Muscle thickness and weight, calf muscle strength, and serum creatine and creatine kinase (CK) levels were then measured. The administration of FS attenuated the decrease in calf thickness, gastrocnemius muscle thickness, muscle strength and weight, fiber diameter and serum lactate dehydrogenase levels in the gastrocnemius muscle bundles which was induced by dexamethasone in a dose-dependent manner. Treatment with FS also prevented the dexamethasone-induced increase in serum creatine and creatine kinase levels, histopathological muscle fiber microvacuolation and fibrosis, and the immunoreactivity of muscle fibers for nitrotyrosine, 4-hydroxynonenal, inducible nitric oxide synthase and myostatin. In addition, the destruction of the gastrocnemius antioxidant defense system was also inhibited by the administration of FS in a dose-dependent manner. FS downregulated the mRNA expression of atrogin-1 and muscle ring-finger protein-1 (involved in muscle protein degradation), myostatin (a potent negative regulator of muscle growth) and sirtuin 1 (a representative inhibitor of muscle regeneration), but upregulated the mRNA expression of phosphatidylinositol 3-kinase, Akt1, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4, involved in muscle growth and the activation of protein synthesis. The overall effects of treatment with 500 mg/kg FS were comparable to those observed following treatment with 50 mg/kg oxymetholone. The results from the present study support the hypothesis that FS has a favorable ameliorating effect on muscle atrophy induced by dexamethasone, by exerting anti-inflammatory and antioxidant effects on muscle fibers, which may be due to an increase in protein synthesis and a decrease in protein degradation.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Força Muscular/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Schisandra/metabolismo , Aldeídos/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Creatina/sangue , Creatina Quinase/sangue , Dexametasona/farmacologia , Fibrose/tratamento farmacológico , Fibrose/prevenção & controle , L-Lactato Desidrogenase/sangue , Camundongos , Camundongos Endogâmicos ICR , Proteínas Musculares/genética , Tono Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Miostatina/biossíntese , Miostatina/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Oximetolona/farmacologia , Fosfatidilinositol 3-Quinase/genética , Biossíntese de Proteínas/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/biossíntese , Receptor A1 de Adenosina/genética , Proteínas Ligases SKP Culina F-Box/genética , Sirtuína 1/genética , Canais de Cátion TRPV/genética , Proteínas com Motivo Tripartido , Tirosina/análogos & derivados , Tirosina/imunologia , Ubiquitina-Proteína Ligases/genética
13.
Cell Signal ; 27(9): 1895-904, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25958325

RESUMO

MicroRNAs (miRNAs or miRs) play a critical role in skeletal muscle development. In a previous study we observed that miR-128 was highly expressed in skeletal muscle. However, its function in regulating skeletal muscle development is not clear. Our hypothesis was that miR-128 is involved in the regulation of the proliferation and differentiation of skeletal myoblasts. In this study, through bioinformatics analyses, we demonstrate that miR-128 specifically targeted mRNA of myostatin (MSTN), a critical inhibitor of skeletal myogenesis, at coding domain sequence (CDS) region, resulting in down-regulating of myostatin post-transcription. Overexpression of miR-128 inhibited proliferation of mouse C2C12 myoblast cells but promoted myotube formation; whereas knockdown of miR-128 had completely opposite effects. In addition, ectopic miR-128 regulated the expression of myogenic factor 5 (Myf5), myogenin (MyoG), paired box (Pax) 3 and 7. Furthermore, an inverse relationship was found between the expression of miR-128 and MSTN protein expression in vivo and in vitro. Taken together, these results reveal that there is a novel pathway in skeletal muscle development in which miR-128 regulates myostatin at CDS region to inhibit proliferation but promote differentiation of myoblast cells.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo/fisiologia , MicroRNAs/metabolismo , Desenvolvimento Muscular/fisiologia , Mioblastos Esqueléticos/metabolismo , Miostatina/biossíntese , Animais , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mioblastos Esqueléticos/citologia , Miostatina/genética
14.
J Appl Physiol (1985) ; 118(12): 1460-6, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25749440

RESUMO

We had the unique opportunity to study the skeletal muscle characteristics, at the single fiber level, of a world champion sprint runner who is the current indoor world record holder in the 60-m hurdles (7.30 s) and former world record holder in 110-m hurdles (12.91 s). Muscle biopsies were obtained from the vastus lateralis at rest and 4 h after a high-intensity exercise challenge (4 × 7 repetitions of resistance exercise). Single muscle fiber analyses were conducted for fiber type distribution (myosin heavy chain, MHC), fiber size, contractile function (strength, speed, and power) and mRNA expression (before and after the exercise bout). The world-class sprinter's leg muscle had a high abundance (24%) of the pure MHC IIx muscle fibers with a total fast-twitch fiber population of 71%. Power output of the MHC IIx fibers (35.1 ± 1.4 W/l) was 2-fold higher than MHC IIa fibers (17.1 ± 0.5 W/l) and 14-fold greater than MHC I fibers (2.5 ± 0.1 W/l). Additionally, the MHC IIx fibers were highly responsive to intense exercise at the transcriptional level for genes involved with muscle growth and remodeling (Fn14 and myostatin). To our knowledge, the abundance of pure MHC IIx muscle fibers is the highest observed in an elite sprinter. Further, the power output of the MHC IIa and MHC IIx muscle fibers was greater than any human values reported to date. These data provide a myocellular basis for the high level of sprinting success achieved by this individual.


Assuntos
Atletas , Fibras Musculares Esqueléticas/fisiologia , Fibras Musculares Esqueléticas/ultraestrutura , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Corrida/fisiologia , Adulto , Biópsia , Teste de Esforço , Expressão Gênica/genética , Expressão Gênica/fisiologia , Humanos , Perna (Membro) , Masculino , Contração Muscular/fisiologia , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Rápida/fisiologia , Fibras Musculares de Contração Rápida/ultraestrutura , Fibras Musculares Esqueléticas/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Miostatina/biossíntese , Miostatina/genética , Educação Física e Treinamento , Receptores do Fator de Necrose Tumoral/genética , Treinamento de Resistência , Natação/fisiologia , Receptor de TWEAK
15.
Muscle Nerve ; 51(3): 434-42, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24916884

RESUMO

INTRODUCTION: We investigated the effect of resistance exercise intensity and exercise-induced metabolic stress on the activation of anabolic signaling and expression of myogenic genes in skeletal muscle. METHODS: Ten strength-trained athletes performed high-intensity [HI, 74% of 1-repetition maximum (RM)], middle-intensity (MI, 54% 1RM), or middle-intensity (54% 1RM) no-relaxation exercise (MIR). Kinase phosphorylation level and myogenic gene expression in muscle samples were evaluated before, 45 min, 5 h, and 20 h after exercise. RESULTS: The lactate concentration in MI was approximately 2-fold lower than in the 2 other sessions, and was highest in MIR. The phosphorylation level of extracellular kinase 1/2Thr202/Tyr204 after exercise was related to metabolic stress. Metabolic stress induced a decrease in myostatin mRNA expression, whereas mechano-growth factor mRNA level depended on exercise intensity. CONCLUSIONS: This study demonstrates that both intensity and exercise-induced metabolic stress can be manipulated to affect muscle anabolic signaling.


Assuntos
Sistema de Sinalização das MAP Quinases/fisiologia , Músculo Esquelético/metabolismo , Miostatina/biossíntese , Treinamento de Resistência/métodos , Fator de Transcrição STAT5/biossíntese , Estresse Fisiológico/fisiologia , Proteínas Supressoras de Tumor/biossíntese , Regulação da Expressão Gênica , Humanos , Masculino , Adulto Jovem
16.
FEBS Lett ; 589(3): 295-301, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25543063

RESUMO

Recent studies demonstrated an association between the K153R polymorphism in the myostatin gene with extreme longevity, lower muscle strength and obesity but the molecular basis of these associations has not been clarified. Here, we show that the K153R mutation significantly increases the rate of proteolysis of promyostatin by furin, but has no effect on the activity of the latent complex or the cleavage of the latent complex by bone morphogenetic protein 1 (BMP-1). The increased rate of activation of K153R mutant promyostatin may explain why this polymorphism is associated with obesity, lower muscle strength and extension of lifespan.


Assuntos
Furina/metabolismo , Longevidade/genética , Miostatina/genética , Obesidade/genética , Envelhecimento/genética , Envelhecimento/patologia , Proteína Morfogenética Óssea 1/metabolismo , Furina/genética , Células HEK293 , Humanos , Força Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Miostatina/biossíntese , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Conformação Proteica
17.
Age (Dordr) ; 36(4): 9699, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25108351

RESUMO

Skeletal muscle satellite cells (SCs) have been shown to be instrumental in the muscle adaptive response to exercise. The present study determines age-related differences in SC content and activation status following a single bout of exercise. Ten young (22 ± 1 years) and 10 elderly (73 ± 1 years) men performed a single bout of resistance-type exercise. Muscle biopsies were collected before and 12, 24, 48, and 72 h after exercise. SC content and activation status were assessed in type I and type II muscle fibers by immunohistochemistry. Myostatin and MyoD protein and messenger RNA (mRNA) expression were determined by Western blotting and rtPCR, respectively. In response to exercise, it took 48 h (young) and 72 h (elderly) for type II muscle fiber SC content to exceed baseline values (P < 0.01). The number of myostatin + SC in type I and II muscle fibers was significantly reduced after 12, 24, and 48 h of post-exercise recovery in both groups (P < 0.01), with a greater reduction observed at 24 and 48 h in the young compared with that in the elderly men (P < 0.01). In conclusion, the increase in type II muscle fiber SC content during post-exercise recovery is delayed with aging and is accompanied by a blunted SC activation response.


Assuntos
Envelhecimento/fisiologia , Tolerância ao Exercício/genética , Regulação da Expressão Gênica , Proteína MyoD/genética , Miostatina/genética , RNA Mensageiro/genética , Células Satélites de Músculo Esquelético/metabolismo , Idoso , Biópsia , Western Blotting , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Proteína MyoD/biossíntese , Miostatina/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Células Satélites de Músculo Esquelético/citologia , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-24875565

RESUMO

Glucocorticoids (GCs) strongly regulate myostatin expression in mammals via glucocorticoid response elements (GREs), and bioinformatics methods suggest that this regulatory mechanism is conserved among many vertebrates. However, the multiple myostatin genes found in some fishes may be an exception. In silico promoter analyses of the three putative rainbow trout (Oncorhynchus mykiss) myostatin promoters have failed to identify putative GREs, suggesting a divergence in myostatin function. Therefore, we hypothesized that myostatin mRNA expression is not regulated by glucocorticoids in rainbow trout. In this study, both juvenile rainbow trout and primary trout myoblasts were treated with cortisol to examine the effects on myostatin mRNA expression. Results suggest that exogenous cortisol does not regulate myostatin-1a and -1b expression in vivo, as myostatin mRNA levels were not significantly affected by cortisol treatment in either red or white muscle tissue. In red muscle, myostatin-2a levels were significantly elevated in the cortisol treatment group relative to the control, but not the vehicle control, at both 12 h and 24 h post-injection. As such, it is unclear if cortisol was acting alone or in combination with the vehicle. Cortisol increased myostatin-1b expression in a dose-dependent manner in vitro. Further work is needed to determine if this response is the direct result of cortisol acting on the myostatin-1b promoter or through an alternative mechanism. These results suggest that regulation of myostatin by cortisol may not be as highly conserved as previously thought and support previous work that describes potential functional divergence of the multiple myostatin genes in fishes.


Assuntos
Hidrocortisona/farmacologia , Miostatina/biossíntese , Regiões Promotoras Genéticas , Transcrição Genética/efeitos dos fármacos , Animais , Simulação por Computador , Regulação da Expressão Gênica/efeitos dos fármacos , Miostatina/efeitos dos fármacos , Oncorhynchus mykiss/crescimento & desenvolvimento , RNA Mensageiro/biossíntese
20.
PLoS One ; 9(1): e87687, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24498167

RESUMO

Growth factors, such as myostatin (Mstn), play an important role in regulating post-natal myogenesis. In fact, loss of Mstn has been shown to result in increased post-natal muscle growth through enhanced satellite cell functionality; while elevated levels of Mstn result in dramatic skeletal muscle wasting through a mechanism involving reduced protein synthesis and increased ubiquitin-mediated protein degradation. Here we show that miR-27a/b plays an important role in feed back auto-regulation of Mstn and thus regulation of post-natal myogenesis. Sequence analysis of Mstn 3' UTR showed a single highly conserved miR-27a/b binding site and increased expression of miR-27a/b was correlated with decreased expression of Mstn and vice versa both in vitro and in mice in vivo. Moreover, we also show that Mstn gene expression was regulated by miR-27a/b. Treatment with miR-27a/b-specific AntagomiRs resulted in increased Mstn expression, reduced myoblast proliferation, impaired satellite cell activation and induction of skeletal muscle atrophy that was rescued upon either blockade of, or complete absence of, Mstn. Consistent with this, miR-27a over expression resulted in reduced Mstn expression, skeletal muscle hypertrophy and an increase in the number of activated satellite cells, all features consistent with impaired Mstn function. Loss of Smad3 was associated with increased levels of Mstn, concomitant with decreased miR-27a/b expression, which is consistent with impaired satellite cell function and muscular atrophy previously reported in Smad3-null mice. Interestingly, treatment with Mstn resulted in increased miR-27a/b expression, which was shown to be dependent on the activity of Smad3. These data highlight a novel auto-regulatory mechanism in which Mstn, via Smad3 signaling, regulates miR-27a/b and in turn its own expression. In support, Mstn-mediated inhibition of Mstn 3' UTR reporter activity was reversed upon miR-27a/b-specific AntagomiR transfection. Therefore, miR-27a/b, through negatively regulating Mstn, plays a role in promoting satellite cell activation, myoblast proliferation and preventing muscle wasting.


Assuntos
Regulação da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Desenvolvimento Muscular/fisiologia , Miostatina/biossíntese , Células Satélites de Músculo Esquelético/metabolismo , Proteína Smad3/metabolismo , Regiões 3' não Traduzidas/fisiologia , Animais , Linhagem Celular , Masculino , Camundongos , Camundongos Mutantes , MicroRNAs/genética , Miostatina/genética , Células Satélites de Músculo Esquelético/citologia , Proteína Smad3/genética
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