Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.006
Filtrar
1.
Food Chem ; 302: 125371, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437711

RESUMO

Dietary selenium deficiency is recognized as a global problem. Pork is the most widely consumed meat throughout the world and an important source of selenium for humans. In this study, a reliable approach was developed for analyzing selenium and its speciation in the muscles of pigs after different selenium treatments. The selenium source deposition efficiency was ranked as: selenomethionine > methylselenocysteine > selenite, and the muscle selenium content had a dose effect with selenomethionine supplementation. In total, four species of selenium were detected in the muscles of pigs and the distributions of these selenium species were greatly affected by the dietary selenium supplementation forms and levels. Selenomethionine (>70% of total selenium) and selenocystine (>11%) were the major selenium species, followed by methylselenocysteine and selenourea. Therefore, selenium-enriched pork produced from selenomethionine is a good source for improving human dietary selenium intake.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Músculo Esquelético/química , Compostos de Selênio/farmacologia , Selênio/análise , Animais , Cistina/análogos & derivados , Cistina/análise , Suplementos Nutricionais , Análise de Alimentos/métodos , Masculino , Músculo Esquelético/efeitos dos fármacos , Compostos Organosselênicos/análise , Reprodutibilidade dos Testes , Ácido Selenioso/farmacologia , Compostos de Selênio/análise , Selenocisteína/análogos & derivados , Selenocisteína/farmacologia , Selenometionina/análise , Selenometionina/farmacologia , Suínos , Ureia/análogos & derivados , Ureia/análise
2.
Braz J Med Biol Res ; 52(10): e8391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596311

RESUMO

The effect of a short-term creatine supplementation on hindlimb suspension (HS)-induced muscle atrophy was investigated. Creatine monohydrate (5 g/kg b.w. per day) or placebo, divided in 2 daily doses, was given by oral gavage for 5 days. Rats were maintained in HS with dietary supplementation concomitantly for 5 days. Body weight, soleus and EDL muscle masses, and cross-sectional areas (CSA) of the muscle fibers were measured. Signaling pathways associated with skeletal muscle mass regulation (FST, MSTN, FAK, IGF-1, MGF, Akt, mTOR, atrogin-1, and MuRF1 expressions, and Akt, S6, GSK3B, and 4EBP1 proteins) were evaluated in the muscles. Soleus muscle exhibited more atrophy than the EDL muscle due to HS. Creatine supplementation attenuated the decrease of wet weight and increased p-4EBP1 protein in the EDL muscle of HS rats. Also, creatine increased mTOR and atrogin-1 expressions in the same muscle and condition. In the absence of HS, creatine supplementation increased FAK and decreased MGF expressions in the EDL muscle. Creatine attenuated the increase in FST expression due to HS in the soleus muscle. MuRF1 expression increased in the soleus muscle due to creatine supplementation in HS animals whereas atrogin-1 expression increased still further in this group compared with untreated HS rats. In conclusion, short-term creatine supplementation changed protein metabolism signaling in soleus and EDL muscles. However, creatine supplementation only slightly attenuated the mass loss of both muscles and did not prevent the CSA reduction and muscle strength decrease induced by HS for 5 days.


Assuntos
Creatina/administração & dosagem , Suplementos Nutricionais , Elevação dos Membros Posteriores/efeitos adversos , Atrofia Muscular/dietoterapia , Animais , Modelos Animais de Doenças , Masculino , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/etiologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
3.
Life Sci ; 236: 116906, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614147

RESUMO

AIMS: The anti-hyperglycemic action of metformin on skeletal muscles is presently unclear. Long noncoding RNAs (lncRNAs) are implicated in multiple cellular functions. This study aims to explore the role of lncRNAs in the glucometabolic action of metformin on skeletal muscle cells. MAIN METHODS: Metformin accumulation was assessed using [14C]-metformin. A lncRNA array was used to investigate metformin-regulated lncRNAs in C2C12 skeletal muscle cells. Knockdown studies were applied to evaluate the function of lncRNA Dreh. A colorimetric assay was used for the measurement of medium glucose concentration; glucose transport was assessed using [3H]-2-deoxyglucose; real-time PCR was used for RNA expression analysis, and western blotting was used to assess protein expression in myotubes. A Dreh overexpression plasmid was transfected into the cells. KEY FINDINGS: Metformin accumulated in C2C12 myotubes. Metformin reduced medium glucose concentration and repressed lncRNA Dreh expression in the myotubes. Knockdown of Dreh in the myotubes resulted in reduced glucose concentration in the culture medium, increased glucose transport, and increased levels of GLUT4 protein in the plasma membrane. Overexpression of Dreh attenuated the glucose-lowering effect of metformin in myotubes. SIGNIFICANCE: The glucoregulatory actions of metformin are mediated in part by a lncRNA, Dreh, in the skeletal muscle cells. Dreh is a novel regulator for glucose transport and could be a therapeutic target for diabetes.


Assuntos
Glucose/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , RNA Longo não Codificante/genética , Animais , Transporte Biológico , Linhagem Celular , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos
4.
Nature ; 574(7776): 63-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554967

RESUMO

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.


Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
5.
Life Sci ; 235: 116800, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472151

RESUMO

AIMS: It is well known that cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD) accompanied by skeletal muscle atrophy. Histone deacetylases (HDACs) that remove acetyl groups from target proteins are necessary for the muscle atrophy associated with skeletal muscle disuse. However, the role of HDACs and trichostatin A (TSA), a HDAC inhibitor, in skeletal muscle atrophy caused by CS exposure remains poorly understood. MAIN METHODS: Female mice were exposed to CS twice daily for 40 days and TSA injected intraperitoneally into CS-exposed mice on alternate days. Skeletal muscles were weighed and gastrocnemius (Gas) muscle histomorphology examined by hematoxylin and eosin staining. Histone deacetylases 1 and 2 (HDAC1/2), and markers of ubiquitin degradation, muscle differentiation, apoptosis, pyroptosis, and the cytoskeletal proteins were assessed by western blot and immunohistochemistry in Gas. KEYFINDINGS: CS exposure decreased body and skeletal muscle weights and triggered an increase in the percentage of fiber with centralized nuclei in Gas. HDAC1/2 proteins were upregulated in the Gas of mice exposed to CS, while TSA effectively inhibited HDAC1/2 protein levels and attenuated the loss of body weight and skeletal muscle wet weight induced by CS exposure. Markers for ubiquitin degradation, muscle differentiation, cytoskeletal proteins, apoptosis and pyroptosis were all upregulated following CS exposure and effectively restored by TSA. SIGNIFICANCE: TSA may inhibit skeletal muscle atrophy and histomorphological alterations induced by CS exposure by downregulating markers of ubiquitin degradation, muscle fiber differentiation, cytoskeletal proteins, apoptosis and pyroptosis via HDAC1/2 inhibition.


Assuntos
Apoptose/efeitos dos fármacos , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Fumar/efeitos adversos , Animais , Proteínas do Citoesqueleto/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia
6.
Adv Exp Med Biol ; 1155: 133-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468392

RESUMO

Metabolic syndrome is a lifestyle-related disease caused by high nutrient condition and lack of exercise. The insulin resistance due to obesity has attracted attention as an underlying mechanism of metabolic syndrome. Insulin resistance refers to reduced insulin sensitivity in insulin target tissues. In this case, in order to maintain normal blood glucose levels, a compensatory large amount of insulin is released, leading to the occurrence of hyperinsulinemia. Taurine is widely distributed in animal tissues. Although it is not involved in protein synthesis, taurine plays an important role in maintaining the body's physiological function. In this experiment, insulin resistance model was induced by high fat and high sugar diet. Two percent taurine was added in drinking water to explore the mechanism of taurine in insulin resistance and to provide theoretical basis for using taurine to improve insulin resistance. The result showed that high-fat and high-sugar diet could decrease insulin sensitivity, and taurine could improve it by oral glucose tolerance test. Moreover, serum TG, TC were higher, while HDL-C in rats fed with high sugar and high fat diet was lower than normal rats, the changes of which can be significantly relieved by 2% taurine administration. mRNA and protein expressions of IRS1, and GLUT4 which were significantly changed by high sugar and high fat diet can also be regulated by 2% taurine. The results indicated that taurine can improve insulin sensitivity through remediating lipid metabolism disorder and regulating the expressions of IRS and GLUT4.


Assuntos
Resistência à Insulina , Metabolismo dos Lipídeos , Músculo Esquelético/efeitos dos fármacos , Taurina/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Açúcares da Dieta/efeitos adversos , Músculo Esquelético/fisiologia , Ratos
7.
Adv Exp Med Biol ; 1155: 359-365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468414

RESUMO

The purpose of this study was to characterize the effects of taurine (supplementation and acute injection) on the stretch reflex in the ankle muscles, and in particular to compare the effects of chronic taurine supplementation versus acute injection on the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle of an awake mouse was stretched at various speeds ranging from 500 to 500,000° per second. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We found that at each velocity, the taurine-fed mice generated more tension and exhibited a higher EMG response. Acute taurine injection did not affect the tension but significantly reduced the EMG. To evaluate if the enhances response was due to neuronal excitability of changes in the passive properties of the muscles, we anesthetize the mice to eliminate the central component of the reflex. Under these conditions, taurine-fed mice still exhibited an enhanced stretch reflex response. We have previously shown that taurine-fed mice have reduced expression of GABAA receptors and other biochemical changes in the GABAergic system that are consistent with hyper-excitability. GABAA receptor is a major component of the inhibitory (GABAergic) system and its reduced expression probably contributes to the enhanced stretch reflex in these mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.


Assuntos
Músculo Esquelético/efeitos dos fármacos , Reflexo de Estiramento , Taurina/farmacologia , Animais , Eletromiografia , Camundongos , Músculo Esquelético/fisiologia , Receptores de GABA/fisiologia
8.
Life Sci ; 232: 116508, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278948

RESUMO

AIM: Fluoxetine, one of the first newer SSRI antidepressant, is an extremely popular treatment for depression that could improve mental health problems. Many recent studies have suggested that SSRI have potential beneficial effects on skeletal muscle tissue. MAIN METHOD: We evaluated the potential beneficial effects of oral fluoxetine (18 mg/kg/day for 6 weeks) on muscle performance, after 6 weeks of physical exercise on treadmill. Male mice were randomly assigned to four groups (n = 12 per group) for treatment. Each group received treatment with following specifications: 1) no exercise with vehicle treatment (SED-S); 2) no exercise with fluoxetine treatment (SED-F); 3) exercise with vehicle treatment (EX-S); and 4) exercise with fluoxetine treatment (EX-F). Exercise performances were assessed based on the exhaustive running time and forelimb grip strength, anxious behavior by elevated plus-maze and open-field tests. Mitochondrial enzymes activity and ROS production were measured in the gastrocnemius and soleus muscles. KEY FINDING: Fluoxetine treatment had a significant effect on maximal aerobic capacity in mice without exercise, but more significant effects on gripping strength and anxiety when combined with exercise training, e.g. increased strength and decreased anxiety. SIGNIFICANCE: Fluoxetine treatment and exercise stimulation also had synergistic effects on strength and increased mitochondrial activity, cellular oxidative and antioxidant capacity in two different muscles.


Assuntos
Fluoxetina/farmacologia , Esforço Físico/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Oxirredução , Estresse Oxidativo , Condicionamento Físico Animal/fisiologia , Resistência Física/efeitos dos fármacos
9.
Food Chem ; 300: 125173, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319335

RESUMO

The administration of anabolic agents in farm animals to improve meat production has been prohibited in EU, due to the potential risks to human health. Meat quality was investigated to detect the effects of illegal administration of dexamethasone or prednisolone or 17ß-estradiol on Charolais bulls. Three groups of 6 bulls were treated and 12 bulls were the control. Meat quality parameters were measured on live animals, carcasses and on samples of Longissimus thoracis and multivariate statistical data analysis was applied. In Charolais bulls, these parameters were affected by growth promoter administration and the multivariate canonical discriminant analysis was able to distinguish between treated and untreated animals mainly due to three electronic nose's parameters, 24 h carcass temperature and drip loss. Therefore, meat quality control and the multivariate analysis could be useful as a first screening to address targeted controls on farms suspected of illicit use of growth promoters.


Assuntos
Análise de Alimentos/métodos , Substâncias de Crescimento/farmacologia , Carne , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/crescimento & desenvolvimento , Animais , Bovinos , Dexametasona/farmacologia , Análise Discriminante , Nariz Eletrônico , Estradiol/farmacologia , Fazendas , Análise de Alimentos/instrumentação , Análise de Alimentos/estatística & dados numéricos , Qualidade dos Alimentos , Masculino , Carne/análise , Prednisolona/farmacologia
10.
Food Chem ; 298: 125030, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31260978

RESUMO

Plant extracts from rosemary (RE), green tea (GTE), and maté (ME) were compared for the protection against iron-induced oxidation in porcine homogenates at total phenolic concentrations from 25 to 250 ppm. Lipid oxidation as indicated by TBARS was in all cases sufficiently suppressed, especially for RE. Hydrophobic RE retarded overall oxidation in the homogenates with an inverted dose-dependent response. Optimum delay of oxygen consumption was found at the lowest concentration applied, similar to protection against thiols and formation of protein radicals as measured by ESR, whereas the high concentration increased oxygen consumption and caused additionally thiol loss possibly due to thiol-quinone interactions, generating protein-phenol complexes. Hydrophilic ME or GTE increased the initial oxygen consumption rate as an indication of prooxidant activities at elevated concentrations. However, they were found to protect myoglobin and protein at those high concentrations with GTE being more efficient, possibly due to better chelation effect.


Assuntos
Antioxidantes/farmacologia , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Relação Dose-Resposta a Droga , Ilex paraguariensis/química , Ferro/química , Ferro/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mioglobina/metabolismo , Oxirredução , Fenóis/metabolismo , Extratos Vegetais/química , Rosmarinus/química , Suínos , Chá/química
11.
Int J Exp Pathol ; 100(3): 175-183, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31321841

RESUMO

Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite with protein anabolic effects. We examined the effects of an HMB-enriched diet in healthy rats and rats with liver cirrhosis induced by multiple doses of carbon tetrachloride (CCl4). HMB increased branched-chain amino acids (BCAAs; valine, leucine and isoleucine) in blood and BCAA and ATP in muscles of healthy animals. The effect on muscle mass and protein content was insignificant. In CCl4-treated animals alterations characteristic of liver cirrhosis were found with decreased ratio of the BCAA to aromatic amino acids in blood and lower muscle mass and ATP content when compared with controls. In CCl4-treated animals consuming HMB, we observed higher mortality, lower body weight, higher BCAA levels in blood plasma, higher ATP content in muscles, and lower ATP content and higher cathepsin B and L activities in the liver when compared with CCl4-treated animals without HMB. We conclude that (1) HMB supplementation has a positive effect on muscle mitochondrial function and enhances BCAA concentrations in healthy animals and (2) the effects of HMB on the course of liver cirrhosis in CCl4-treated rats are detrimental. Further studies examining the effects of HMB in other models of hepatic injury are needed to determine pros and cons of HMB in the treatment of subjects with liver cirrhosis.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Valeratos/farmacologia , Animais , Tetracloreto de Carbono/metabolismo , Suplementos Nutricionais , Leucina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Ratos Wistar
12.
BMC Complement Altern Med ; 19(1): 165, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286941

RESUMO

BACKGROUND: Rosmarinic acid (RA) is a natural pure compound from herbs belonging to the Lamiaceae family, such as rosemary, sage, basil, and mint. The antioxidant, angiotensin-converting enzyme inhibitory, and vasodilatory effects of RA have been revealed. Angiotensin II (ANG II) is a potent agent that generates hypertension and oxidative stress. Hypertension and skeletal muscle insulin resistance are strongly related. The aim of this study was to evaluate the effects of acute and chronic RA treatment on blood pressure and skeletal muscle glucose transport in ANG II-induced hypertensive rats. METHODS: Eight-week-old male Sprague Dawley rats were separated into SHAM and ANG II-infused (250 ng/kg/min) groups. ANG II rats were treated with or without acute or chronic RA at 10, 20, or 40 mg/kg. At the end of the experiment, body weight, liver and heart weights, oral glucose tolerance, skeletal muscle glucose transport activity, and signaling proteins were evaluated. RESULTS: Both acute and chronic RA treatment decreased systolic, diastolic, and mean arterial blood pressure. Only acute RA at 40 mg/kg resulted in a reduction of fasting plasma glucose levels and an induction of skeletal muscle glucose transport activity. These effects might involve increased ERK activity in skeletal muscle. Meanwhile, chronic RA treatment with 10, 20, and 40 mg/kg prevented ANG II-induced hyperglycemia. CONCLUSIONS: Both acute and chronic RA treatment attenuated ANG II-induced cardiometabolic abnormalities in rats. Therefore, RA would be an alternative strategy for improving skeletal muscle glucose transport and protecting against ANG II-induced hypertension and hyperglycemia.


Assuntos
Cinamatos/farmacologia , Depsídeos/farmacologia , Glucose/metabolismo , Hipertensão/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Angiotensina II , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
13.
Arch Physiol Biochem ; 125(5): 470-477, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31291133

RESUMO

Context: Skeletal muscle atrophy is a complication of diabetes, partially induced by nicotinamide adenine dinucleotide (NAD+) deficiency. Objective: This study investigates the potential of nicotinamide (NAM) supplementation, a precursor of NAD+, against muscle atrophy. Methods: Mice were separated into normal control group, normal control with NAM administration group, diabetic group, and diabetic mice with NAM administration group. Basic characteristics, muscle weight, maximal grip strength, and myofibers cross-sectional area were analysed. Markers reflecting muscle atrophy and hypertrophy, and transforming growth factor ß1/Smad2 (TGF-ß1/Smad2) pathway were examined. Results: NAM did not influence body weight and blood glucose. In diabetic mice, NAM increased NAD+ level, rescued muscle weight and strength loss, and increased myofibers cross-sectional area. NAM inhibited MuRF1 and Atrogin1, while elevated phosphorylation of Akt. Overactivation of TGF-ß1/Smad2 pathway was repressed by NAM. Conclusion: NAM ameliorated diabetic muscle atrophy by rebalancing protein anabolism and catabolism, probably through de-activation of TGF-ß1/Smad2 signaling.


Assuntos
Diabetes Mellitus Experimental/complicações , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/complicações , Atrofia Muscular/prevenção & controle , Niacinamida/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Endocrinology ; 160(10): 2417-2426, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31322699

RESUMO

In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A-induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (-16%) and lean mass (-10%). In agreement with previous findings, we demonstrated that adeno-associated virus-mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.


Assuntos
Ativinas/toxicidade , Caquexia/induzido quimicamente , Peptídeos/farmacologia , Animais , Células CHO , Caquexia/prevenção & controle , Cricetinae , Cricetulus , Rim/efeitos dos fármacos , Rim/patologia , Fígado/patologia , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Miocárdio , Tamanho do Órgão/efeitos dos fármacos , Peptídeos/química
15.
Zhonghua Shao Shang Za Zhi ; 35(5): 333-340, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31154730

RESUMO

Objective: To explore the effects of insulin therapy on skeletal muscle wasting (SMW) in severely scalded rats and its related mechanism. Methods: Totally 48 male Wistar rats aged 7-8 weeks were divided into simple scald (SS) group and insulin therapy (IT) group according to the random number table, with 24 rats in each group. After weighing the body mass and measuring the blood glycemic level of the tail end with a glucometer, the rats in the two groups were immersed in hot water at 94 ℃ for 12 seconds to make a full-thickness dorsal scald model involving 30% total body surface area. Rats in group IT were subcutaneously injected with 1 U/kg insulin glargine at 8: 00 a day from post injury day (PID) 1 to 7, whilst rats in group SS were given the same amount of normal saline. Rats in the two groups were given 10 mL/kg enteral nutritional emulsion by intragastric infusion at 8: 00 (after insulin administration), 13: 00, and 18: 00 a day respectively from PID 1 to 7. The blood glycemic levels of tail end of rats in the two groups were measured by glucometer before insulin administration on PID 1-4, 6, and 7 and on every morning of PID 8, 9, 11, 12, and 14. The body mass of rats in the two groups on PID 14 without any treatment was weighed. Eight rats from each group were collected respectively on PID 4, 7, and 14 to harvest tibialis anterior muscle (TAM) samples. The mass of TAM on PID 14 was weighed. The ultrastructural changes of TAM myocytes on PID 7 were observed with transmission electron microscope. The apoptotic rates of TAM myocytes on PID 4, 7, and 14 were assessed by the assay of terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphate-biotin nick end labeling, the expressions of cysteine-aspartic protease-3 (caspase-3) of TAM on PID 4, 7, and 14 were detected with immunohistochemistry, and protein expressions of endoplasmic reticulum (ER) stress (ERS) associated proteins glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein-homologous protein (CHOP), and activated caspase-12 of TAM on PID 4, 7, and 14 were detected with Western blotting. Data were processed with completely random design t test, analysis of variance for repeated measurement, analysis of variance for factorial design, t test, and Bonferroni correction. Results: The blood glycemic level and body mass of rats in the two groups before injury were similar (t=0.204, 0.405, P>0.05). There were no statistically significant differences in blood glycemic levels of rats between the two groups on PID 1, 6, 9, 11, 12, and 14 (t=0.229, 3.339, 1.610, 0.178, 0.181, 0.079, P>0.05). Compared with those of group SS, blood glycemic levels of rats in group IT were significantly lower on PID 2, 3, 4, 7, and 8 (t=7.245, 4.165, 4.609, 4.018, 3.995, P<0.05 or P<0.01). On PID 14, the body mass and TAM mass of rats in group IT were (271±19) g and (0.47±0.05) g respectively, both obviously higher than (254±12) g and (0.43±0.04) g of group SS (t=2.159, 2.375, P<0.05). On PID 7, nuclear pyknosis and deformation, chromosome misdistribution, and ER swelling in TAM myocytes of rats in group SS were observed; the apoptotic alterations and ER swelling of TAM myocytes were alleviated in rats of group IT as compared with those of group SS. The apoptotic rates of TAM myocytes of rats in group IT were obviously lower than those of group SS on PID 4, 7, and 14 (t=4.262, 9.153, 9.799, P<0.01). The expressions of caspase-3 in TAM of rats in group IT were obviously lower than those of group SS on PID 7 and 14 (t=10.429, 7.617, P<0.01). Compared with those of group SS, the protein expressions of GRP78 were obviously increased on PID 4 and 14 (t=4.172, 4.437, P<0.05), the protein expressions of activated caspase-12 were obviously decreased on PID 7 and 14 (t=11.049, 11.181, P<0.01), and the protein expressions of CHOP were obviously decreased on PID 4, 7, and 14 (t=13.837, 9.572, 6.930, P<0.01) in TAM of rats in group IT. Conclusions: Insulin therapy may reduce skeletal muscle myocytes apoptosis and SMW by alleviating ERS in rats with severe scald.


Assuntos
Queimaduras/tratamento farmacológico , Insulina/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Síndrome de Emaciação , Animais , Insulina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar
16.
Zhonghua Shao Shang Za Zhi ; 35(5): 341-350, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31154731

RESUMO

Objective: To observe how glutamine affect the skeletal muscle membrane repair in severely burned mice through promoting the mitsugumin 53 (MG53) dimerization in skeletal muscle and to explore its functional mechanism. Methods: (1) Animal experiments. A total of 179 BALB/c male mice aged 6 to 8 weeks were divided into sham injury group (n=43), burn group (n=73) and burn+ glutamine group (n=63) according to the random number table (the same grouping method below). Mice in sham injury group were sham injured on the back, and mice in burn group and burn+ glutamine group were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burn) on the back. Mice in burn+ glutamine group were intragastrically administered with glutamine (1 mg/kg), and the other two groups were given the same amount of amino acid solution once per day for 14 days. On post burn hour 12, 10 mice from burn group were taken for preparation of burn serum, which is used in the following cell experiments. Blood samples were collected from the hearts to prepare serum from 10 mice in sham injury group immediately after burn and from 10 mice in burn group and burn+ glutamine group on post burn day (PBD) 5, 10, and 14, respectively. And then the whole gastrocnemius muscle was harvested after the mice were sacrificed. On PBD 10, the whole flexor brevis digitorum was harvested from 6 mice in the 3 groups respectively after the mice were sacrificed. On PBD 5, 10, and 14, the whole gastrocnemius muscle tissue was harvested from another 9 mice in the 3 groups respectively after the mice were sacrificed. The mass of the whole gastrocnemius muscle of mice was weighed. The total protein content of gastrocnemius muscle of mice was detected by coomassie brilliant blue method. The repair function of myolemma of flexor brevis digitorum of mice was detected by two-photon laser fiber membrane perforating. The serum content of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) of mice was determined with radioimmunoassay. The expressions of MG53 dimer and monomer in gastrocnemius of mice were determined with non-reductive electrophoresis-Western blotting. The protein expressions of endoplasmic reticulum stress sign proteins CCAAT/enhancer binding protein homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) in gastrocnemius of mice were determined with Western blotting. (2) Cell experiments. Mice skeletal muscle precursor cells C2C12 were cultured in vitro, and cells of the second passage were selected for the experiments. The cells were divided into normal control group, burn serum group, and burn serum+ glutamine group, with 3 dishes in each group and 1×10(3) cells in each dish. Cells in normal control group were cultured with 1 mL Dulbecco's modified Eagle medium (DMEM) with fetal bovine serum of volume fraction 10%, cells in burn serum group were cultured with 1 mL DMEM with burn serum of volume fraction 10%, and cells in burn serum+ glutamine group were cultured with 1 mL DMEM with burn serum of volume fraction 10% and 4 µL glutamine with a final molar concentration of 8 mmol/L. After 24 hours of culturing, the repair function of myocyte membrane after differentiation of skeletal muscle precursor cells in mice was detected with the same method before. Another cells were grouped and cultured as before, with 3 wells in each group and 1×10(5) cells in each well. After 24 hours of culturing, the expressions of MG53 dimer and monomer and endoplasmic reticulum stress marker proteins in the cells were detected as before. Data were processed with analysis of variance of factorial design, one-way analysis of variance, least significant difference t test, and Student Newman Keuls test. Results: Animal experiments. (1) Compared with those in sham injury group, the mass and total protein content of gastrocnemius muscle of mice in burn group were significantly decreased on PBD 5, 10, and 14 (P<0.05). Compared with those in burn group, the mass and total protein content of gastrocnemius muscle of mice in burn+ glutamine group were significantly increased on PBD 5, 10, and 14 (P<0.05). (2) Compared with that in sham injury group (0.9±0.4), the fluorescence intensity of FM1-43 in myofiber of mice in burn group (7.8±0.4) was significantly increased on PBD 10 (t=7.75, P<0.05). Compared with that in burn group, the fluorescence intensity of FM1-43 in myofiber of mice in burn+ glutamine group (4.0±0.4) was significantly decreased on PBD 10 (t=-4.31, P<0.05). (3) Compared with that in sham injury group, the serum content of TNF-α and IL-6 of mice in burn group was significantly increased on PBD 5, 10, and 14 (P<0.05). Compared with that in burn group, the serum content of TNF-α and IL-6 of mice in burn+ glutamine group was significantly decreased on PBD 5, 10, and 14 (P<0.05). (4) Compared with 56.97±2.82, 44.89±4.72, 42.46±1.06, 14.26±0.99, 62.36±2.74, and 29.45±0.84 in sham injury group, the expressions of MG53 dimer and monomer in gastrocnemius of mice were significantly decreased in burn group on PBD 5, 10, and 14 (6.16±0.25, 26.09±1.22, 28.86±1.53, 5.63±0.25, 26.74±0.79, 4.41±0.52, P<0.05). Compared with those in burn group, the expression of MG53 dimer of gastrocnemius of mice in burn+ glutamine group was significantly increased on PBD 10 and 14 (36.79±1.44, 43.96±1.62), and the expression of MG53 monomer of gastrocnemius muscle of mice in burn+ glutamine group was significantly increased on PBD 14 (13.16±2.17, P<0.05). Compared with those in sham injury group, the protein expressions of CHOP and GRP78 in gastrocnemius muscle of mice in burn group were significantly elevated on PBD 5, 10, and 14 (P<0.05). Compared with those in burn group, the protein expressions of CHOP and GRP78 in gastrocnemius of mice in burn+ glutamine group were significantly reduced on PBD 5, 10 (P<0.05). Cell experiments. (1) Compared with that in normal control group (1.76±0.25), the fluorescence intensity of FM1-43 in cells in burn serum group (9.46±1.22) was significantly increased after 24 hours of culturing (t=12.28, P<0.05). Compared with that in burn serum group, the fluorescence intensity of FM1-43 in cells in burn serum+ glutamine group (4.71±0.45) was significantly decreased after 24 hours of culturing (t=-7.59, P<0.05). (2) The expressions of MG53 monomer of cells were similar in normal control group, burn serum group, and burn+ glutamine group after 24 hours of culturing (P>0.05). Compared with 58.5±1.8 in normal control group, the expression of MG53 dimer of cells in burn serum group was significantly decreased after 24 hours of culturing (14.1±1.4, P<0.05). Compared with that in burn serum group, the expression of MG53 dimer of cells in burn serum+ glutamine group was significantly increased after 24 hours of culturing (30.9±0.6, P<0.05). Compared with those in normal control group, the protein expressions of CHOP and GRP78 of cells were significantly elevated in burn serum group after 24 hours of culturing (P<0.05). Compared with those in burn serum group, the protein expressions of CHOP and GRP78 of cells were significantly reduced in burn serum+ glutamine group after 24 hours of culturing (P<0.05). Conclusions: Glutamine can promote MG53 dimerization by alleviating endoplasmic reticulum stress in severely burned mice. Thus it can accelerate skeletal muscle membrane repair, reduce the local inflammatory reaction of skeletal muscle and consumption of skeletal muscle.


Assuntos
Queimaduras/tratamento farmacológico , Glutamina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Animais , Proteínas de Transporte , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley
17.
J Frailty Aging ; 8(3): 154-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237318

RESUMO

BACKGROUND: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue in people living with HIV, however, the effects on skeletal muscle fat and area are unknown. OBJECTIVES: The goals of this exploratory secondary analysis were to determine the effects of tesamorelin on muscle quality (density) and quantity (area). DESIGN: Secondary, exploratory analysis of two previously completed randomized (2:1), clinical trials. SETTING: U.S. and Canadian sites. PARTICIPANTS: People living with HIV and with abdominal obesity. Tesamorelin participants were restricted to responders (visceral adipose tissue decrease ≥8%). INTERVENTION: Tesamorelin or placebo. MEASUREMENTS: Computed tomography scans (at L4-L5) were used to quantify total and lean density (Hounsfield Units, HU) and area (centimeters2) of four trunk muscle groups using a semi-automatic segmentation image analysis program. Differences between muscle area and density before and after 26 weeks of tesamorelin or placebo treatment were compared and linear regression models were adjusted for baseline and treatment arm. RESULTS: Tesamorelin responders (n=193) and placebo (n=148) participants with available images were similar at baseline; most were Caucasian (83%) and male (87%). In models adjusted for baseline differences and treatment arm, tesamorelin was associated with significantly greater increases in density of four truncal muscle groups (coefficient 1.56-4.86 Hounsfield units; all p<0.005), and the lean anterolateral/abdominal and rectus muscles (1.39 and 1.78 Hounsfield units; both p<0.005) compared to placebo. Significant increases were also seen in total area of the rectus and psoas muscles (0.44 and 0.46 centimeters2; p<0.005), and in the lean muscle area of all four truncal muscle groups (0.64-1.08 centimeters2; p<0.005). CONCLUSIONS: Among those with clinically significant decrease in visceral adipose tissue on treatment, tesamorelin was effective in increasing skeletal muscle area and density. Long term effectiveness of tesamorelin among people with and without HIV, and the impact of these changes in daily life should be further studied.


Assuntos
Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Infecções por HIV/epidemiologia , Músculo Esquelético/efeitos dos fármacos , Adulto , Canadá/epidemiologia , Feminino , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Humanos , Masculino
18.
Gen Physiol Biophys ; 38(3): 237-244, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31184310

RESUMO

Hyperglycemia impairs oxidative capacity in skeletal muscle. Muscle oxidative capacity is regulated by peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α). Transcutaneous carbon dioxide (CO2) enhances PGC-1α expression in skeletal muscle. Therefore, the aim of this study was to clarify the effects of CO2 therapy on muscle oxidative capacity impaired by streptozotocin (STZ)-induced hyperglycemia. Eight-week-old male Wistar rats were randomly divided into 4 groups: control, CO2 treatment, STZ-induced hyperglycemia, and STZ-induced hyperglycemia treated with CO2. STZ-induced hyperglycemia resulted in a decrease of muscle oxidative capacity and decreased PGC-1α and cytochrome c oxidase subunit 4 (COX-4) expression levels; while, application of transcutaneous CO2 attenuated this effect, and enhanced the expression levels of endothelial nitric oxide synthesis (eNOS). These results indicate that transcutaneous CO2 improves impaired muscle oxidative capacity via enhancement of eNOS and PGC-1α-related signaling in the skeletal muscle of rats with hyperglycemia.


Assuntos
Dióxido de Carbono/administração & dosagem , Dióxido de Carbono/farmacologia , Hiperglicemia/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Administração Cutânea , Animais , Modelos Animais de Doenças , Masculino , Oxirredução/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar
19.
Nat Commun ; 10(1): 2430, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160583

RESUMO

Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) - a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients.


Assuntos
Tecido Adiposo/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Células-Tronco/citologia , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo/patologia , Adolescente , Idade de Início , Animais , Anexina A2/metabolismo , Estudos de Casos e Controles , Disferlina/genética , Venenos Elapídicos/toxicidade , Feminino , Fibrose , Humanos , Técnicas In Vitro , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Inibidores de Proteases/farmacologia , Índice de Gravidade de Doença , Células-Tronco/efeitos dos fármacos , Tiofenos/farmacologia , Adulto Jovem
20.
Chin Med J (Engl) ; 132(12): 1461-1466, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31205105

RESUMO

BACKGROUND: Low handgrip strength (HS) and declining gait speed (GS) are increasingly obvious with aging, requiring effective, and safe medication for treatment. Trimetazidine (TMZ) modified release tablets, a common anti-angina drug, has potential benefits for alleviating the condition, but this has not yet been fully studied and therefore is the aim of this study. METHODS: This is a prospective randomized controlled study. Fifty-eight eligible patients will be randomly assigned to one of two study groups: TMZ group or control group. For the TMZ group, a dose of 35 mg of oral TMZ will be administered with a meal twice a day for 3 months, in addition to any conventional treatments for angina. Only conventional treatments for angina will be administrated in the control group. The primary outcome will be the 6-min walking distance and the secondary outcomes will be: muscle strength (HS and pinch strength), GS, muscle endurance (five times sit-to-stand test), balance maintenance (tandem standing test), and the frequency of angina per week. Additionally, body mass index, circumferences (biceps, waist, hip, and calf), albumin levels, and the score on a five-question scale for sarcopenia will be obtained during the study. DISCUSSION: This study aims to evaluate the usefulness of TMZ in a population with poor muscle function. The results may provide an effective and safe medical treatment to people with low muscle strength or physical performance. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800015000; www.chictr.org.cn/showproj.aspx?proj=25445.


Assuntos
Angina Estável/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Trimetazidina/uso terapêutico , Vasodilatadores/uso terapêutico , Idoso , Angina Estável/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA