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1.
J Sci Food Agric ; 99(15): 6788-6795, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31368537

RESUMO

BACKGROUND: Myostatin (MSTN) negatively regulates skeletal muscle development; however, its functions in internal organs have not been thoroughly investigated. Here, we compared the morphological, molecular, and biological characteristics of the heart, liver, spleen, lungs, kidneys, and tongue of homozygous MSTN mutant (MSTN-/- ), heterozygous MSTN mutant (MSTN+/- ), and wild-type (WT) piglets. RESULTS: The heart and liver were lighter in MSTN-/- piglets than in MSTN+/- piglets, while the tongue was heavier in MSTN-/- piglets than in WT piglets (P < 0.05). Furthermore, the tongue was longer in MSTN-/- piglets than in WT piglets, and myofibers of the tongue were significantly larger in the former piglets than in the latter ones (P < 0.01). mRNA expression of MSTN in all organs was significantly lower in MSTN-/- and MSTN+/- piglets than in WT piglets (P < 0.05). Meanwhile, mRNA expression of follistatin, which is closely related to MSTN, in the heart and liver was significantly higher in MSTN-/- piglets than in MSTN+/- and WT piglets (P < 0.05). In addition, protein expression of MSTN in the heart, kidneys, and tongue was significantly lower in MSTN-/- piglets than in WT piglets (P < 0.01). CONCLUSION: These results suggest that MSTN is widely expressed and has marked effects in multiple internal organs. Myostatin has crucial functions in regulating internal organ size, especially the tongue. © 2019 Society of Chemical Industry.


Assuntos
Estruturas Animais/crescimento & desenvolvimento , Animais Geneticamente Modificados/crescimento & desenvolvimento , Miostatina/genética , Suínos/crescimento & desenvolvimento , Suínos/genética , Estruturas Animais/metabolismo , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Folistatina/genética , Folistatina/metabolismo , Mutação , Miostatina/metabolismo , Tamanho do Órgão , Suínos/metabolismo
2.
J Med Ultrason (2001) ; 46(4): 377-388, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377938

RESUMO

PURPOSE: Low-intensity pulsed ultrasound (LIPUS) is effective in promoting bone healing, and a myostatin deficiency also has a positive effect on bone formation. In this study, we evaluated the effects of LIPUS on bone healing in rats in vivo and investigated the mechanisms in vitro, aiming to explore whether LIPUS promotes bone healing through inhibition of the myostatin signaling pathway. METHODS: Rats with both drill-hole defects and MC3T3-E1 cells were randomly assigned to a LIPUS group and a control group. The LIPUS group received LIPUS treatment (1.5 MHz, 30 mW/cm2) for 20 min/day. RESULTS: After 21 days, the myostatin expression in quadriceps was significantly inhibited in the LIPUS group, and remodeling of the newly formed bone in the drill-hole site was significantly better in the LIPUS group than that in the control group, which was confirmed by micro-CT analysis. After 3 days, LIPUS significantly promoted osteoblast proliferation; inhibited the expression of AcvrIIB (the myostatin receptor), Smad3, p-Smad3, and GSK-3ß; and increased Wnt1 and ß-catenin expression. Moreover, translocation of ß-catenin from the cytolemma to the nucleus was observed in the LIPUS group. However, these effects were blocked by treatment with myostatin recombinant protein. CONCLUSIONS: The results indicate that LIPUS may promote bone healing through inhibition of the myostatin signal pathway.


Assuntos
Consolidação da Fratura/fisiologia , Fraturas Ósseas/terapia , Miostatina/metabolismo , Transdução de Sinais/fisiologia , Terapia por Ultrassom/métodos , Animais , Western Blotting , Técnicas de Cultura de Células , Modelos Animais de Doenças , Feminino , Fraturas Ósseas/diagnóstico por imagem , Reação em Cadeia da Polimerase , Ratos , Ratos Sprague-Dawley , Tomografia Computadorizada por Raios X , Ondas Ultrassônicas
3.
Chem Commun (Camb) ; 55(62): 9108-9111, 2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31298230

RESUMO

Inhibition of myostatin is an attractive treatment for muscular dystrophy and other amyotrophic diseases. A myostatin-binding peptide was functionalized by equipped with an on/off switchable photo-oxygenation catalyst. This peptide induces a selective oxygenation of myostatin under near-infrared light, resulting in inactivation of myostatin. This peptide shows several orders of magnitude greater inhibitory effect than the original peptide.


Assuntos
Miostatina/efeitos dos fármacos , Miostatina/efeitos da radiação , Oxigênio/química , Oxigênio/efeitos da radiação , Peptídeos/farmacologia , Processos Fotoquímicos/efeitos da radiação , Catálise/efeitos dos fármacos , Catálise/efeitos da radiação , Humanos , Raios Infravermelhos , Modelos Moleculares , Estrutura Molecular , Miostatina/metabolismo , Peptídeos/química
4.
Poult Sci ; 98(11): 5265-5271, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265735

RESUMO

Myostatin (MSTN) is a negative regulator of skeletal muscle growth and plays an important role in muscle development. In this research, we constructed a tissue expression profile of the pigeon MSTN gene in eight tissues and a spatio-temporal expression profile in the pectoral muscle using qRT-PCR method. And the pectoralis muscle fiber traits during pigeon post-hatching stages at 1, 7, 14, 21, and 28 D were analyzed through the paraffin sections. Then the correlations between the muscle fiber diameter, cross-sectional area, density, and the expression of MSTN in the pectoral muscle were analyzed. Results showed that MSTN mRNA was mainly expressed in breast muscle, heart, spleen, and kidney and it was almost unexpressed in the liver and lungs. Moreover, the MSTN mRNA expression level in breast muscle was significantly higher than that in other tissues (P < 0.05), and showed an interesting trend that it decreased in the first week and then increased with age. Meanwhile, decrease of myostatin transcripts was accompanied by the down-regulation of Myf5 and the up-regulation of MyoG during the first week post-hatching. In addition, the paraffin sections analysis results revealed that the diameter and cross-sectional area of pectoralis muscle fiber significantly increased with age (P < 0.05), and a significant positive correlation was shown between the MSTN gene expression level and muscle fiber diameter (P < 0.05). These fundamental researches might contribute to further understanding of the roles MSTN played in the post-hatching muscle fiber development in pigeon.


Assuntos
Proteínas Aviárias/genética , Columbidae/crescimento & desenvolvimento , Columbidae/genética , Fibras Musculares Esqueléticas/metabolismo , Miostatina/genética , Músculos Peitorais/crescimento & desenvolvimento , Animais , Proteínas Aviárias/metabolismo , Feminino , Miostatina/metabolismo
5.
Georgian Med News ; (289): 47-50, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31215878

RESUMO

In patients with chronic renal failure receiving hemodialysis, the development of protein-energy wasting (PEW) has a significant impact on the quality and duration of life. Myostatin (MSTN) and protein kinase-ß (AKT) play an important role in this process. The aim of our study was to assess the contribution of these molecular markers of muscle metabolism to the development of PEW in patients with chronic kidney disease stage 5D (CKD5D). The study included 80 patients with CKD5D. All patients underwent anthropometric research, hand dynamometry, bio-impedancemetry. MSTN and AKT levels were determined in the blood by ELISA. In the study, the prevalence of PEW was 90%. We have proposed a catabolic muscle tissue index (CMTI), which takes into account the complex effect of the relationship between MSTN and AKT on the development of PEW. An increase in this index in degrees from 0-2 characterizes the prevalence of catabolic processes in muscle tissue. There is an increase in CMTI with the progression of nutritional disorders in patients on hemodialysis (HD). An increase in CMTI is associated with a decrease in muscle strength, muscle mass (measured by the diameter of the shoulder). No correlation was found between CMTI and gender, age, or bio-impedance indicators, which requires further investigation.


Assuntos
Falência Renal Crônica , Músculo Esquelético , Miostatina , Desnutrição Proteico-Calórica , Proteínas Proto-Oncogênicas c-akt , Humanos , Falência Renal Crônica/metabolismo , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Estado Nutricional , Desnutrição Proteico-Calórica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Diálise Renal
6.
Acta Histochem ; 121(5): 539-545, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31047685

RESUMO

This study investigated the effects of a CoCl2-simulated hypoxic environment on the muscle fiber switching signaling pathways calcineurin A/nuclear factor of activated T cells cytoplasmic 1 (CnA/NFATc1) and myostatin. In this study, C2C12 muscle cells were cultured in vitro under CoCl2-simulated chemical hypoxic conditions, the expression levels of CnA and myostatin were detected through qRT-PCR and Western blot analyses, and a positioning study of NFATc1 was carried out by immunofluorescence labeling. Results showed that CoCl2 treatment significantly increased the expression levels of CnA and myostatin. Moreover, the position of NFATc1 expression changed; actually, its expression in the nucleus considerably increased. Furthermore, CoCl2-induced hypoxia inhibited the differentiation of C2C12 cells and reduced the expression levels of many slow- and fast-twitch muscles marker genes, but immunofluorescence staining results showed that the proportion of MyHC I type muscle fiber increased after CoCl2 treatment. The hypoxic environment simulated by CoCl2 can activate the signaling pathways CnA/NFATc1 and myostatin and increases the proportion of MyHC I type muscle fibers.


Assuntos
Calcineurina/metabolismo , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Fatores de Transcrição NFATC/metabolismo , Animais , Western Blotting , Hipóxia Celular/fisiologia , Células Cultivadas , Cobalto , Camundongos , Miostatina/genética , Fatores de Transcrição NFATC/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Transcriptoma
7.
Diabetes Res Clin Pract ; 152: 156-165, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31102684

RESUMO

AIM: To investigate the effect of a single and 15 units of high-intensity circuit training (HICT) programme on glucose metabolism, myokines' response and selected genes' expression in women. METHODS: Thirty-three, non-active women (mean age: 38 ±â€¯12) were split into a HICT (n = 20) or a control group (CON, n = 13). The training protocol included three circuits of nine exercises with own body weight as a workload performed 3 times a week for five weeks. The CON group performed HICT twice. Blood samples were taken before, 1 h and 24 h after the first and last unit to determine IGF-1, myostatin, irisin, decorin, HSP27, interleukin-15 concentrations using the ELISA immunoenzymatic method. To evaluate HSPB1, TNF-α and DCN mRNA, real-time PCR was used. Pre- and post-intervention, the oral glucose test and body composition assessment were completed. RESULTS: The following parameters tended to decrease after the 5-week HICT program: insulin and HOMA-IR Training diminished insulin/IGF-1 ratio (51% CI: -63% to -34%) and induced the drop of myostatin concentration but significantly only among middle-aged women and at baseline insulin resistance. CONCLUSION: Obtained data revealed that HICT improved an insulin sensitivity and diminished myostatin concentration among older, insulin-resistant women with lower baseline physical capacity.


Assuntos
Envelhecimento/fisiologia , Exercícios em Circuitos , Terapia por Exercício/métodos , Tolerância ao Exercício/fisiologia , Resistência à Insulina/fisiologia , Aptidão Física/fisiologia , Adulto , Fatores Etários , Glicemia/metabolismo , Composição Corporal/fisiologia , Exercícios em Circuitos/métodos , Decorina/genética , Decorina/metabolismo , Metabolismo Energético/genética , Exercício/fisiologia , Feminino , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Pessoa de Meia-Idade , Miostatina/genética , Miostatina/metabolismo , Treinamento de Resistência/métodos , Adulto Jovem
8.
J Anim Sci ; 97(8): 3199-3212, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31115451

RESUMO

This study assessed cellular characteristics of longissimus lumborum (LL) and semitendinosus (ST) muscles in steers genetically selected for low (Low) or high (High) muscling using live muscle scoring, and High steers with 1 copy of the loss-of-function 821 del11 MSTN allele (HighHet). We hypothesized High and HighHet have altered muscle cellular characteristics and mechanisms influencing muscling compared with Low steers. Angus steers 25 mo old comprising 14 High, 19 Low, and 11 HighHet were backgrounded to 20 mo of age, grain finished for 150 d, and then slaughtered. Body and carcass weights did not differ due to muscling line (P = 0.46). Weight of LL was 16% greater (P = 0.004) and total protein in LL was 18% greater (P = 0.012) in HighHet than Low steers. ST weight in HighHet was 10% and 13% greater than in High and Low steers (P = 0.007), respectively, and of total ST protein 12% and 17% greater in HighHet than High or Low (P = 0.002). Cross-sectional area (CSA) of LL was greater in HighHet than in High and greater in High than in Low (85.0 vs. 77.0 vs. 70.4 cm2, P < 0.001). Apparent number of myofibers and myofibers per unit CSA did not differ between the muscling lines in LL (P = 0.14) or ST (P = 0.47). Myofiber CSA was greater in the ST of Low than of High and HighHet for type 1 (36% and 31% respectively, P = 0.005) and 2A (22% and 25%, P < 0.001). HighHet steers had greater area of glycolytic (type 2X) relative to more oxidative myofiber types within LL (P = 0.02; 11% and 43% more than High and Low, respectively) and ST (P < 0.001; 27% and 75%). Concentration of RNA in LL was 13% and 10% greater (P = 0.005) in High than in Low and HighHet, respectively, and total amount of RNA in LL was 22% greater in High and 20% greater in HighHet than in Low (P < 0.001). The LL of High steers had less protein to RNA (P = 0.03; 57.4 vs. 65.6) and more RNA to DNA (P = 0.007; 9.03 vs. 7.83) than Low. HighHet steers had 11% more DNA in ST than High (P = 0.04) and 19% more RNA in ST than Low (P = 0.012). The shift towards glycolytic myofibers was consistent with loadings in a principal component that explained 39% of the variation in LL and 38% in ST. Overall, these findings show that selection for increased muscling using live cattle muscle scoring, and 1 copy of the 821 del11 MSTN allele, results in more glycolytic muscle. They also suggest that increased muscling of the High compared with Low steers may be associated with increased translational capacity in the LL.


Assuntos
Bovinos/fisiologia , Miostatina/genética , Carne Vermelha/normas , Alelos , Animais , Bovinos/genética , Bovinos/crescimento & desenvolvimento , Estudos de Coortes , Glicólise , Mutação com Perda de Função , Masculino , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Oxirredução , RNA/metabolismo
9.
PLoS One ; 14(4): e0215298, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30998775

RESUMO

Myostatin (MSTN) negatively regulates skeletal muscle growth, and its activity is inhibited by the binding of MSTN propeptide (MSTNpro), the N-terminal domain of proMSTN that is proteolytically cleaved from the proMSTN. Partial sequences from the N-terminal side of MSTNpro have shown to be sufficient to inhibit MSTN activity. In this study, to determine the minimum size of flatfish MSTNpro for MSTN inhibition, various truncated forms of flatfish MSTNpro with N-terminal maltose binding protein (MBP) fusion were expressed in E. coli and purified. MSTNpro regions consisting of residues 45-68, -69, and -70 with MBP fusion suppressed MSTN activity with a potency comparable to that of full-sequence flatfish MSTNpro in a pGL3-(CAGA)12-luciferase reporter assay. Even though the MSTN-inhibitory potency was about 1,000-fold lower, the flatfish MSTNpro region containing residues 45-65 (MBP-Pro45-65) showed MSTN-inhibitory capacity but not the MBP-Pro45-64, indicating that the region 45-65 is the minimum domain required for MSTN binding and suppression of its activity. To examine the in vivo effect of MBP-fused, truncated flatfish MSTNpro, MBP-Pro45-70-His6 (20 mg/kg body wt) was subcutaneously injected 5 times for 14 days in mice. Body wt gain and bone mass were not affected by the administration. Grip strength and swimming time were significantly enhanced at 7 d after the administration. At 14 d, the effect on grip strength disappeared, and the extent of the effect on swimming time significantly diminished. The presence of antibody against MBP-Pro45-70-His6 was observed at both 7 and 14 d after the administration with the titer value at 14 d being much greater than that at 7 d, suggesting that antibodies against MBP-Pro45-70-His6 neutralized the MSTN-inhibitory effect of MBP-Pro45-70-His6. We, thus, examined the MSTN-inhibitory capacity and in vivo effect of flatfish MSTNpro region 45-65 peptide (Pep45-65-NH2), which was predicted to have no immunogenicity in silico analysis. Pep45-65-NH2 suppressed MSTN activity with a potency similar to that of MBP-Pro45-65 but did not suppress GDF11, or activin A. Pep45-65-NH2 blocked MSTN-induced Smad2 phosphorylation in HepG2 cells. The administration of Pep45-65 (20 mg/kg body wt, 5 times for 2 weeks) increased the body wt gain with a greater gain at 14 d than at 7 d and muscle wt. Grip strength and swimming time were also significantly enhanced by the administration. Antibody titer against Pep45-65 was not detected. In conclusion, current results indicate that MSTN-inhibitory proteins with heterologous fusion partner may not be effective in suppressing MSTN activity in vivo due to an immune response against the proteins. Current results also show that the region of flatfish MSTNpro consisting of 45-65 (Pep45-65) can suppress mouse MSTN activity and increase muscle mass and function without invoking an immune response, implying that Pep45-65 would be a potential agent to enhance skeletal muscle growth and function in animals or to treat muscle atrophy caused by various clinical conditions.


Assuntos
Proteínas de Peixes/farmacologia , Linguados , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/crescimento & desenvolvimento , Miostatina/antagonistas & inibidores , Peptídeos/farmacologia , Animais , Proteínas de Peixes/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miostatina/metabolismo , Peptídeos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia
10.
J Biol Chem ; 294(16): 6333-6343, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30814254

RESUMO

Growth differentiation factor 8 (GDF8; also known as myostatin) and GDF11 are closely related members of the transforming growth factor ß (TGF-ß) family. GDF8 strongly and negatively regulates skeletal muscle growth, and GDF11 has been implicated in various age-related pathologies such as cardiac hypertrophy. GDF8 and GDF11 signaling activities are controlled by the extracellular protein antagonists follistatin; follistatin-like 3 (FSTL3); and WAP, follistatin/kazal, immunoglobulin, Kunitz, and netrin domain-containing (WFIKKN). All of these proteins contain a follistatin domain (FSD) important for ligand binding and antagonism. Here, we investigated the structure and function of the FSD from murine WFIKKN2 and compared it with the FSDs of follistatin and FSTL3. Using native gel shift and surface plasmon resonance analyses, we determined that the WFIKKN2 FSD can interact with both GDF8 and GDF11 and block their interactions with the type II receptor activin A receptor type 2B (ActRIIB). Further, we solved the crystal structure of the WFIKKN2 FSD to 1.39 Å resolution and identified surface-exposed residues that, when substituted with alanine, reduce antagonism of GDF8 in full-length WFIKKN2. Comparison of the WFIKKN2 FSD with those of follistatin and FSTL3 revealed differences in both the FSD structure and position of residues within the domain that are important for ligand antagonism. Taken together, our results indicate that both WFIKKN and follistatin utilize their FSDs to block the type II receptor but do so via different binding interactions.


Assuntos
Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas de Transporte/química , Fatores de Diferenciação de Crescimento/antagonistas & inibidores , Miostatina/antagonistas & inibidores , Receptores de Activinas Tipo II/química , Receptores de Activinas Tipo II/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/química , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Proteínas Relacionadas à Folistatina/química , Proteínas Relacionadas à Folistatina/metabolismo , Fatores de Diferenciação de Crescimento/química , Fatores de Diferenciação de Crescimento/metabolismo , Células HEK293 , Humanos , Camundongos , Miostatina/química , Miostatina/metabolismo , Ressonância de Plasmônio de Superfície
11.
Res Vet Sci ; 124: 200-211, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30921567

RESUMO

Myostatin (MSTN) was identified as a negative regulator of skeletal muscle growth. MSTN inhibition by myostatin propeptide (MSPP) increased skeletal muscle mass, myofiber growth and muscle force. Thus, this study was designed to produce wild-type porcine MSPP (WT-MSPP) and its mutated form (D75A-MSPP) in yeast Pichia pastoris and to investigate its potential enhancement of myoblast growth and differentiation. In an in vitro study, C2C12 myoblasts were treated with the purified WT-MSPP or D75A-MSPP (10 µg/mL) in either a regular culture medium or in a differentiation medium for 72 h. In an animal trial, post-weaning C57BL/6 mice fed with a high-fat diet (HFD) were administered WT-MSPP or D75A-MSPP for 6 weeks. The results showed that C2C12 myoblasts treated with the purified WT-MSPP or D75A-MSPP could dramatically promote cell proliferation. Both myoD and myogenin were significantly increased (p < .05) after WT-MSPP or D75A-MSPP treatment. D75A-MSPP was particularly more effective than WT-MSPP in promoting myotube formation (p < .05). The post-weaning mice treated with D75A-MSPP significantly increased both body and muscle weights compared with the mock and WT-MSPP groups (p < .05). Furthermore, the mice treatment with D75A-MSPP could prevent increased glucose injection from inducing glucose elevation. Our data indicated that a mutant-type MSPP (D75A-MSPP) was superior to WT-MSPP in effectively enhancing myofiber growth due to the highly resistant to proteolytic cleavage by the bone morphogenetic protein-1/tolloid (BMP-1/TLD) and thus has potential applications for clinical muscle wasting diseases or for increasing muscle mass in meat-producing animals.


Assuntos
Intolerância à Glucose/veterinária , Mioblastos/fisiologia , Miostatina/metabolismo , Pichia/genética , Sus scrofa/fisiologia , Doenças dos Suínos/tratamento farmacológico , Animais , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/tratamento farmacológico , Pichia/metabolismo , Proteínas Recombinantes/metabolismo , Suínos
12.
Skelet Muscle ; 9(1): 8, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922397

RESUMO

BACKGROUND: Cancer cachexia as a metabolic syndrome can lead to at least 25% of cancer deaths. The inhibition of muscle atrophy is a main strategy to treat cancer cachexia. In this process, myostatin (MSTN) can exert a dual effect on protein metabolism, including inhibition of protein biosynthesis and enhancement of protein degradation. In this study, we will test the effect on muscle atrophy induced by cancer cachexia of IMB0901, a MSTN inhibitor. METHODS: Two high-throughput screening models against MSTN were developed. By screening, IMB0901, 2-((1-(3,4-dichlorophenyl)-1H-pyrazolo [3,4-d] pyrimidin-4-yl) amino) butan-1-ol, was picked out from the compound library. The in vitro cell model and the C26 animal model of muscle atrophy induced by cancer cachexia were used to determine the pharmacological activity of IMB0901. Whether IMB0901 could inhibit the aggravating effect of doxorubicin on muscle wasting was examined in vitro and in vivo. RESULTS: IMB0901 inhibited the MSTN promoter activity, the MSTN signaling pathway, and the MSTN positive feedback regulation. In atrophied C2C12 myotubes, IMB0901 had a potent efficiency of decreasing MSTN expression and modulating MSTN signaling pathway which was activated by C26-conditioned medium (CM). In C2C12 myotubes, the expressions of three common myotube markers, myosin heavy chain (MyHC), myogenic differentiation 1 (MyoD), and myogenin (MyoG), were downregulated by CM, which could be efficiently reversed by IMB0901 via reduction of ubiquitin-mediated proteolysis and enhancement of AKT/mTOR-mediated protein synthesis. In the C26 animal model, IMB0901 mitigated the weight loss of body, quadricep and liver, and protected the quadriceps cell morphology. Furthermore, IMB0901 decreased the expression of two E3 ligases Atrogin-1 and MuRF-1 in the quadriceps in vivo. At the cellular level, IMB0901 had no influence on anti-tumor effect of three chemotherapeutic agents (cisplatin, doxorubicin, and gemcitabine) and lowered doxorubicin-induced upregulation of MSTN in C2C12 myotubes. IMB0901 did not affect the inhibitory effect of doxorubicin on C26 tumor and delayed the weight loss of muscle and adipose tissue caused by C26 tumor and doxorubicin. CONCLUSIONS: IMB0901 inhibits muscle atrophy induced by cancer cachexia by suppressing ubiquitin-mediated proteolysis and promoting protein synthesis. These findings collectively suggest that IMB0901 is a promising leading compound for the management of muscle atrophy induced by cancer cachexia.


Assuntos
Caquexia/complicações , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Miostatina/antagonistas & inibidores , Miostatina/metabolismo , Neoplasias/complicações , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Doxorrubicina/farmacologia , Células HEK293 , Humanos , Proteínas Musculares/metabolismo , Atrofia Muscular/etiologia , Regiões Promotoras Genéticas , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
13.
Geroscience ; 41(1): 1-11, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30729414

RESUMO

Growth differentiation factor 11 (GDF11) is a transforming growth factor ß (TGFß) protein that regulates aspects of central nervous system (CNS) formation and health throughout the lifespan. During development, GDF11 influences CNS patterning and the genesis, differentiation, maturation, and activity of new cells, which may be primarily dependent on local production and action. In the aged brain, exogenous, peripherally delivered GDF11 may enhance neurogenesis and angiogenesis, as well as improve neuropathological outcomes. This is in contrast to a predominantly negative influence on neurogenesis in the developing CNS. Seemingly antithetical effects may correspond to the cell types and mechanisms activated by local versus circulating concentrations of GDF11. Yet undefined, distinct mechanisms of action in young and aged brains may also play a role, which could include differential receptor and binding partner interactions. Exogenously increasing circulating GDF11 concentrations may be a viable approach for improving deleterious aspects of brain aging and neuropathology. Caution is warranted, however, since GDF11 appears to negatively influence muscle health and body composition. Nevertheless, an expanding understanding of GDF11 biology suggests that it is an important regulator of CNS formation and fate, and its manipulation may improve aspects of brain health in older organisms.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Encéfalo/crescimento & desenvolvimento , Fatores de Diferenciação de Crescimento/fisiologia , Longevidade/fisiologia , Neurogênese , Fator de Crescimento Transformador beta/fisiologia , Animais , Composição Corporal/efeitos dos fármacos , Padronização Corporal/efeitos dos fármacos , Padronização Corporal/fisiologia , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/farmacologia , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/farmacologia , Humanos , Desenvolvimento Muscular/efeitos dos fármacos , Desenvolvimento Muscular/fisiologia , Miostatina/genética , Miostatina/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Homologia de Sequência de Aminoácidos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia
14.
Mol Ther ; 27(3): 600-610, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30765322

RESUMO

Activin A and myostatin, members of the transforming growth factor (TGF)-ß superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.


Assuntos
Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Proteína Smad2/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miostatina/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Proteína Smad2/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
J Bone Miner Metab ; 37(5): 920-927, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30790083

RESUMO

Despite the presence of vitamin D receptor (VDR) in skeletal muscle cells, the relationship between VDR expressions and muscle mass or function has not been well studied. The purpose of this study was to compare VDR gene and protein expression in the forearm muscle between sarcopenic and non-sarcopenic individuals who have sustained distal radius fractures. Twenty samples of muscle tissue from sarcopenic patients (mean age 63.4 ± 8.1 years) and 20 age- and sex-matched control tissues (62.1 ± 7.9 years) were acquired from the edge of dissected pronator quadratus muscle during surgery for distal radius fractures. The mRNA expression levels of VDR as well as the myokines of interest that may be associated with muscle mass change (myogenin and myostatin) were analyzed with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, Western blot assay and immunohistochemistry for VDR were performed. Sarcopenic patients showed a significantly lower level of gene expression for VDR and myogenin, but a greater level of gene expression for myostatin than the controls according to qRT-PCR analysis. The density of VDR protein expressions was 2.1 times greater, while that of myostatin was 2.6 times lower, in the control group than in the sarcopenic group according to Western blot analysis. On immunohistochemical analysis, the density of the cells expressing VDR was significantly decreased in the sarcopenic patients. Sarcopenic patients who sustained distal radius fractures presented lower vitamin D receptor gene and protein expression in skeletal muscles compared to non-sarcopenic individuals.


Assuntos
Regulação da Expressão Gênica , Músculo Esquelético/metabolismo , Fraturas do Rádio/genética , Receptores de Calcitriol/genética , Sarcopenia/genética , Feminino , Antebraço , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Miogenina/genética , Miogenina/metabolismo , Miostatina/genética , Miostatina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fraturas do Rádio/patologia , Receptores de Calcitriol/metabolismo , Sarcopenia/complicações , Sarcopenia/patologia
16.
Acta Histochem ; 121(3): 323-329, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30777303

RESUMO

Myostatin (MSTN) is a key negative regulator of muscle growth and development. Skeletal, cardiac, and smooth muscles were isolated from MSTN knockout (MSTN-∕-) and control mice to investigate the effect of knocking out MSTN on peroxisome proliferator-activated receptor 1 coactivator (PGC-1α)-III and fibronectin domain 5 (FNDC5) expression. Various molecular biology techniques were used to analyze the changes in PGC-1α-FNDC5 in different muscle types from MSTN-∕- mice. The expression levels of PGC-1α and FNDC5 in the skeletal, cardiac, and smooth muscles of MSTN-∕- mice differed from those in the skeletal, cardiac, and smooth muscles of normal mice. This study revealed that knocking out MSTN resulted in inconsistent PGC-1α and FNDC5 expression in specific muscles. It proved for the first time that MSTN deletion attenuated the expression of PGC-1α and FNDC5 in three different murine muscle types. MSTN deletion may have additional effects on the status ofFNDC5 expression. Further research, however, is needed to confirm this conclusion.


Assuntos
Fibronectinas/metabolismo , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Camundongos , Condicionamento Físico Animal/fisiologia , Fatores de Transcrição/metabolismo
17.
Anim Sci J ; 90(4): 504-512, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30663181

RESUMO

We investigated the effect of a system for fattening steers combining grazing with feeding rice whole-crop silage (rWCS) on growth performance, meat characteristics, and the expression of genes involved in skeletal muscle growth. Steers were randomly assigned to grazing or concentrate-fed groups (CT). The grazing group (GZ) was fed rWCS after grazing until 16 months of age. The final body weight was the same in the two groups, but the dressed weight was lower in the GZ than in the CT. The beef color standard was higher in the GZ than in the CT. Although beef marbling did not differ between the two groups, there was less intramuscular fat and subcutaneous fat in the GZ than in the CT. The α-tocopherol and ß-carotene contents in the muscle were higher in the GZ than in the CT. The GZ showed a lower daily gain (DG) during the grazing period, which may have resulted from decelerating skeletal muscle growth caused by the increased expression of genes encoding myostatin and atrogin-1. However, the DG and feed efficiency of the GZ increased after grazing. The two groups exhibited a similar level of beef productivity.


Assuntos
Bovinos/crescimento & desenvolvimento , Bovinos/genética , Dieta/veterinária , Qualidade dos Alimentos , Expressão Gênica , Herbivoria , Músculo Esquelético/crescimento & desenvolvimento , Oryza , Carne Vermelha , Silagem , Tecido Adiposo/metabolismo , Animais , Peso Corporal , Bovinos/metabolismo , Cor , Masculino , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miostatina/genética , Miostatina/metabolismo , alfa-Tocoferol/metabolismo , beta Caroteno/metabolismo
18.
Equine Vet J ; 51(5): 625-633, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30604488

RESUMO

BACKGROUND: Race distance aptitude in Thoroughbred horses is highly heritable and is influenced largely by variation at the myostatin gene (MSTN). OBJECTIVES: In addition to MSTN, we hypothesised that other modifying loci contribute to best race distance. STUDY DESIGN: Using 3006 Thoroughbreds, including 835 'elite' horses, which were >3 years old, had race records and were sampled from Europe/Middle-East, Australia/New Zealand, North America and South Africa, we performed genome-wide association (GWA) tests and separately developed a genomic prediction algorithm to comprehensively catalogue additive genetic variation contributing to best race distance. METHODS: 48,896 single-nucleotide polymorphism (SNP) genotypes were generated from high-density SNP genotyping arrays. Heritability estimates, tests of GWA and genomic prediction models were derived for the phenotypes: average race distance, best race distance for elite, nonelite and all winning horses. RESULTS: Heritability estimates were high ( h m 2  = 0.51, best race distance - elite; h m 2  = 0.42, best race distance - nonelite; h m 2  = 0.40, best race distance - all) and most of the variation was attributed to the MSTN gene. MSTN locus SNPs were the most strongly associated with the trait and included BIEC2-438999 (ECA18:66913090; P = 4.51 × 10-110 , average race distance; P = 2.33 × 10-42 , best race distance - elite). The genomic prediction algorithm enabled the inclusion of variation from all SNPs in a model that partitioned horses into short and long cohorts following assignment of MSTN genotype. Additional genes with minor contributions to best race distance were identified. MAIN LIMITATIONS: The nongenetic influence of owner/trainer decisions on placement of horses in suitable races could not be controlled. CONCLUSIONS: MSTN is the single most important genetic contributor to best race distance in the Thoroughbred. Employment of genetic prediction models will lead to more accurate placing of horses in races that are best suited to their inherited genetic potential for distance aptitude.


Assuntos
Cavalos/genética , Miostatina/metabolismo , Polimorfismo de Nucleotídeo Único , Esportes , Distribuição Animal , Animais , Estudo de Associação Genômica Ampla , Cavalos/fisiologia , Miostatina/genética , Condicionamento Físico Animal , Resistência Física
19.
J Physiol Sci ; 69(2): 235-244, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30259391

RESUMO

We tested the hypothesis that there are sex differences in hindlimb unloading-induced activation of the forkhead box subfamily O3a (FoxO3a) signaling pathway in rat soleus muscle. Age-matched male and female Wistar rats were subjected to hindlimb unloading, and the soleus muscle was removed before or 1 or 7 days after unloading. Female rats showed greater percent changes in relative soleus muscle weight than males. FoxO3a phosphorylation was lower in females than in males and was associated with higher levels of protein ubiquitination 7 days after unloading. Heat shock protein 72 (Hsp72) levels were lower in female rats and increased in males during unloading. Female rats showed slightly higher myostatin levels, which showed a non-significant decline in male rats following unloading. Thus, males and females show different responses to the FoxO3a/ubiquitin-proteasome pathway following hindlimb unloading in rat soleus muscle, which may be associated with differences in Hsp72 expression and myostatin signaling.


Assuntos
Proteína Forkhead Box O3/metabolismo , Membro Posterior/metabolismo , Membro Posterior/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Transdução de Sinais/fisiologia , Animais , Feminino , Proteínas de Choque Térmico HSP72/metabolismo , Elevação dos Membros Posteriores/fisiologia , Masculino , Miostatina/metabolismo , Fosforilação/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Wistar , Caracteres Sexuais , Ubiquitina/metabolismo
20.
Appl Physiol Nutr Metab ; 44(4): 381-388, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30222937

RESUMO

The aim of the present study was to investigate how myostatin dysfunction affects fast and slow muscle stiffness and viscosity during severe repeated loading. Isolated extensor digitorum longus (EDL) and soleus muscles of young adult female mice of the BEH (dysfunctional myostatin) and BEH+/+ (functional myostatin) strains were subjected to 100 contraction-stretching loading cycles during which contractile and mechanical properties were assessed. BEH mice exhibited greater exercise-induced muscle damage, although the effect was muscle- and age-dependent and limited to the early phases of simulated exercise. The relative reduction of the EDL muscle isometric force recorded during the initial 10-30 loading cycles was greater in BEH mice than in BEH+/+ mice and exceeded that of the soleus muscle of either strain. The induced damage was associated with lower muscle stiffness. The effects of myostatin on the mechanical properties of muscles depend on muscle type and maturity.


Assuntos
Contração Isométrica , Fusos Musculares/metabolismo , Força Muscular , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Fatores Etários , Animais , Feminino , Genótipo , Homozigoto , Camundongos Mutantes , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/patologia , Miostatina/deficiência , Miostatina/genética , Fenótipo , Fatores de Tempo , Viscosidade
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