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1.
DNA Cell Biol ; 42(1): 43-52, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36576412

RESUMO

Skeletal muscle mass is closely related to strength and health. Multiple genes and signaling pathways are involved in the regulation of skeletal muscle hypertrophy. miR-29 can participate in various processes of skeletal muscle development through different target genes. However, studies are needed on the function of miR-29 in skeletal muscle during mouse puberty. We used mice in which overexpression of miR-29ab1 cluster could be induced specifically within skeletal muscle, and investigated the effects of miR-29 overexpression on skeletal muscle at 1 month of age. We found that the overexpression of miR-29ab1 cluster in juvenile mice caused skeletal muscle mass and myofiber cross-sectional area to increase. The study on the mechanism of miR-29 inducing skeletal muscle hypertrophy had found that miR-29 achieved its function by inhibiting the expression of Mstn. At the same time, injured myofibers were present within miR-29ab1 cluster overexpressing skeletal muscle. The damage of skeletal muscle may be due to the inhibition of the type IV collagen by miR-29. These results indicate that although the overexpression of miR-29ab1 cluster can induce skeletal muscle hypertrophy in mouse juvenile, it simultaneously causes skeletal muscle damage.


Assuntos
MicroRNAs , Músculo Esquelético , Camundongos , Animais , Músculo Esquelético/metabolismo , Transdução de Sinais , Hipertrofia/genética , Hipertrofia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Miostatina/genética , Miostatina/metabolismo
2.
J Agric Food Chem ; 71(1): 499-511, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36563293

RESUMO

Neoruscogenin is a plant-origin sapogenin that has the potential to modulate muscle growth among the small-molecule compounds that we previously predicted by artificial intelligence to target myostatin (MSTN). This study aimed to elucidate the biological role of neoruscogenin on muscle growth and its relationship with MSTN. Using molecular biological techniques, we found that neoruscogenin inhibited MSTN maturation, thereby repressing its signal transduction; further facilitated protein synthesis metabolism and reduced protein degradation metabolism, ultimately promoting the differentiation of myoblasts and hypertrophy of muscle fibers; and had the effect of repairing muscle injury. This study enriched the biological functions of neoruscogenin and provided a theoretical basis for the treatment of human myopathy and its application in the livestock industry.


Assuntos
Miostatina , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Miostatina/genética , Miostatina/metabolismo , Inteligência Artificial , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Hipertrofia , Músculo Esquelético/metabolismo
3.
Int J Mol Sci ; 23(24)2022 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-36555347

RESUMO

Myostatin (MSTN) is an important negative regulator of skeletal muscle growth in animals. A lack of MSTN promotes lipolysis and glucose metabolism but inhibits oxidative phosphorylation (OXPHOS). Here, we aimed to investigate the possible mechanism of MSTN regulating the mitochondrial energy homeostasis of skeletal muscle. To this end, MSTN knockout mice were generated by the CRISPR/Cas9 technique. Expectedly, the MSTN null (Mstn-/-) mouse has a hypermuscular phenotype. The muscle metabolism of the Mstn-/- mice was detected by an enzyme-linked immunosorbent assay, indirect calorimetry, ChIP-qPCR, and RT-qPCR. The resting metabolic rate and body temperature of the Mstn-/- mice were significantly reduced. The loss of MSTN not only significantly inhibited the production of ATP by OXPHOS and decreased the activity of respiratory chain complexes, but also inhibited key rate-limiting enzymes related to the TCA cycle and significantly reduced the ratio of NADH/NAD+ in the Mstn-/- mice, which then greatly reduced the total amount of ATP. Further ChIP-qPCR results confirmed that the lack of MSTN inhibited both the TCA cycle and OXPHOS, resulting in decreased ATP production. The reason may be that Smad2/3 is not sufficiently bound to the promoter region of the rate-limiting enzymes Idh2 and Idh3a of the TCA cycle, thus affecting their transcription.


Assuntos
Mitocôndrias , Músculo Esquelético , Miostatina , Fosforilação Oxidativa , Animais , Camundongos , Trifosfato de Adenosina/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Miostatina/genética , Miostatina/metabolismo
4.
J Sports Sci Med ; 21(4): 616-624, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36523894

RESUMO

Resistance exercise (RE) activates cell signaling pathways associated with myostatin. Decorin is located in the extracellular matrix (ECM) and can block the inhibitory effect of myostatin. This study sought to determine the impact of low-load (LL) and high-load (HL) RE on myostatin mRNA and protein expression along with changes in muscle decorin and circulating follistatin. Ten resistance-trained men performed a LL (50% 1RM) and HL (80% 1RM) RE session using the angled leg press and leg extension with load and volume equated. Venous blood samples and muscle biopsies were obtained prior to and at 3h and 24h following each RE session. Muscle myostatin mRNA expression was increased at 24h post-exercise (p = 0.032) in LL and at 3h (p = 0.044) and 24h (p = 0.003) post-exercise in HL. Muscle decorin was increased at 24h post-exercise (p < 0.001) in LL and HL; however, muscle myostatin was increased at 24h post-exercise (p < 0.001) only in HL. For muscle Smad 2/3, no significant differences were observed (p > 0.05). Serum follistatin was increased and myostatin decreased at 24h post-exercise (p < 0.001) in LL and HL. Muscle myostatin gene and protein expression increased in response to HL RE. However, serum myostatin was decreased in the presence of increases in decorin in muscle and follistatin in circulation. Therefore, our data suggest a possible mechanism may exist where decorin within the ECM is able to bind to, and decrease, myostatin that might otherwise enter the circulation for activin IIB (ACTIIB) receptor binding and subsequent canonical signaling through Smad 2/3.


Assuntos
Decorina , Exercício Físico , Miostatina , Humanos , Masculino , Decorina/genética , Decorina/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Folistatina/genética , Folistatina/metabolismo , Músculo Esquelético/fisiologia , Miostatina/genética , Miostatina/metabolismo , Treinamento de Força , RNA Mensageiro/genética , Exercício Físico/fisiologia
5.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430183

RESUMO

Myostatin (Mstn) is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes. The deletion of the Mstn gene in mice leads to reduced mitochondrial functions. However, the underlying regulatory mechanisms remain unclear. In this study, we used CRISPR/Cas9 to generate myostatin-knockout (Mstn-KO) mice via pronuclear microinjection. Mstn-KO mice exhibited significantly larger skeletal muscles. Meanwhile, Mstn knockout regulated the organ weights of mice. Moreover, we found that Mstn knockout reduced the basal metabolic rate, muscle adenosine triphosphate (ATP) synthesis, activities of mitochondrial respiration chain complexes, tricarboxylic acid cycle (TCA) cycle, and thermogenesis. Mechanistically, expressions of silent information regulator 1 (SIRT1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) were down-regulated, while peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) acetylation modification increased in the Mstn-KO mice. Skeletal muscle cells from Mstn-KO and WT were treated with AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR), and the AMPK inhibitor Compound C, respectively. Compared with the wild-type (WT) group, Compound C treatment further down-regulated the expression or activity of pAMPK, SIRT1, citrate synthase (CS), isocitrate dehydrogenase (ICDHm), and α-ketoglutarate acid dehydrogenase (α-KGDH) in Mstn-KO mice, while Mstn knockout inhibited the AICAR activation effect. Therefore, Mstn knockout affects mitochondrial function by inhibiting the AMPK/SIRT1/PGC1α signaling pathway. The present study reveals a new mechanism for Mstn knockout in regulating energy homeostasis.


Assuntos
Proteínas Quinases Ativadas por AMP , Miostatina , Camundongos , Animais , Miostatina/genética , Miostatina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Camundongos Knockout , Músculo Esquelético/metabolismo , Aminoimidazol Carboxamida/farmacologia , Mitocôndrias/genética , Mitocôndrias/metabolismo
6.
BMC Pediatr ; 22(1): 632, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329412

RESUMO

Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment.


Assuntos
Atrofia Muscular Espinal , Miostatina , Animais , Criança , Pré-Escolar , Humanos , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Miostatina/genética , Miostatina/metabolismo , Miostatina/uso terapêutico , Ensaios Clínicos Fase II como Assunto
7.
Nutrients ; 14(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36296958

RESUMO

BACKGROUND: Inflammaging is considered to drive loss of muscle function. Omega-3 fatty acids exhibit anti-inflammatory properties. Therefore, we examined the effects of eight weeks of vibration and home-based resistance exercise combined with a whey-enriched, omega-3-supplemented diet on muscle power, inflammation and muscle biomarkers in community-dwelling old adults. METHODS: Participants were randomized to either exercise (3x/week, n = 20), exercise + high-protein diet (1.2-1.5 g/kg, n = 20), or exercise + high-protein and omega-3-enriched diet (2.2 g/day, n = 21). Muscle power (watt/m2) and chair rise test (CRT) time (s) were assessed via CRT measured with mechanography. Furthermore, leg strength (kg/m2) and fasting concentrations of inflammatory (interleukin (IL-) 6, IL-10, high-mobility group box-1 (HMGB-1)) and muscle biomarkers (insulin-like growth factor (IGF-) 1, IGF-binding protein-3, myostatin) were assessed. RESULTS: Sixty-one participants (70.6 ± 4.7 years; 47% men) completed the study. According to generalized linear mixed models, a high-protein diet improved leg strength and CRT time. Only IGF-1 increased with additional omega-3. Sex-specific analyses revealed that muscle power, IL-6, IL-6/IL-10 ratio, and HMGB-1 improved significantly in the male high-protein, omega-3-enriched group only. CONCLUSION: Vibration and home-based resistance exercise combined with a high-protein, omega-3-enriched diet increased muscle power and reduced inflammation in old men, but not in old women. While muscle biomarkers remained unchanged, a high-protein diet combined with exercise improved leg strength and CRT time.


Assuntos
Dieta Rica em Proteínas , Ácidos Graxos Ômega-3 , Treinamento de Força , Feminino , Humanos , Masculino , Biomarcadores/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Proteínas HMGB/metabolismo , Proteínas HMGB/farmacologia , Inflamação/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Força Muscular , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Projetos Piloto , Vibração , Idoso
8.
Int J Chron Obstruct Pulmon Dis ; 17: 2383-2399, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36185172

RESUMO

Objective: Skeletal muscle dysfunction is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD), and is associated with poor quality of life and reduced survival, but the mechanisms involved remain elusive. Ferroptosis is a newly discovered type of cell death resulting from iron-dependent lipid peroxide accumulation. The purpose of this study was to examine whether ferroptosis is involved in COPD-associated skeletal muscle dysfunction. Methods: A mouse model of COPD was established after 24 weeks of cigarette smoke (CS) exposure, and mRNA sequencing, hematoxylin-eosin (H&E) staining, immunostaining (IF), RT-PCR, and Western blot were utilized to identify the changes in gastrocnemius muscles. In vitro, C2C12 myotubes were treated with CS extract (CSE) and evaluated for ferroptosis-related molecules. The pathways regulating ferroptosis were then explored in CSE-stimulated myotubes. Results: Compared with controls, COPD mice showed an enriched ferroptosis pathway. Gpx4 was decreased, while hypoxia-inducible factor (Hif) 2α was increased, at gene and protein levels. A reduced level of GSH, but increased cell death, Fe2+, lipid ROS, LPO, and 4-HNE were observed in COPD mice or in CSE-stimulated C2C12 myotubes, which could be ameliorated by ferroptosis inhibitors. The expression of myostatin (MSTN) was enhanced in COPD mice and CSE-stimulated myotubes. MSTN up-regulated HIF2α expression and led to ferroptosis in myotubes, whereas inhibition of MSTN binding to its receptor or inhibition/knockdown of HIF2α resulted in decreased cell death, and partially restored GPX4 and GSH. Conclusion: CS exposure induced ferroptosis in vivo and in vitro. Mechanistically, CS-exposure upregulated MSTN which further induced ferroptosis through HIF2α in skeletal muscles, which may contribute to muscle dysfunction through impairing metabolic capacity and decreasing muscle fiber numbers, revealing a potential novel therapeutic target for COPD-related skeletal muscle dysfunction.


Assuntos
Ferroptose , Doença Pulmonar Obstrutiva Crônica , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/uso terapêutico , Hematoxilina/metabolismo , Hematoxilina/uso terapêutico , Ferro , Peróxidos Lipídicos/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Miostatina/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
J Nutr Health Aging ; 26(10): 945-953, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36259583

RESUMO

OBJECTIVES: To evaluate the effect of L-carnitine (LC) in combination with leucine supplementation on muscle strength and muscle hypertrophy in aged women participating in a resistance exercise training (RET) program. DESIGN/SETTING/PARTICIPANTS: Thirty-seven out of sixty (38.3% dropout) healthy women aged 60-75 years (mean 67.6 ± 0.7 years) completed the intervention in one of three groups. One of the supplemented groups received 1 g of L-carnitine-L-tartrate in combination with 3 g of L-leucine per day (LC+L group; n = 12), and the second supplemented group received 4 g of L-leucine per day (L group; n = 13). The control group (CON group; n = 12) received no supplementation. INTERVENTION: All three groups completed the same RET protocol involving exercise sessions twice per week for 24 weeks. MEASUREMENTS: Before and after the experiment, participants performed isometric and isokinetic muscle strength testing on the Biodex dynamometer. The cross-sectional areas of the major knee extensors and total thigh muscles were assessed using magnetic resonance imaging. Fasting serum levels of insulin-like growth factor-1 (IGF-1), myostatin and decorin, and plasma levels of total carnitine (TC) and trimethylamine-N-oxide (TMAO) levels were measured. RESULTS: The 24-week RET significantly increased muscle strength and muscle volume, but the group and time interactions were not significant for the muscle variables analyzed. Plasma total carnitine increased only in the LC+L group (p = 0.009). LC supplementation also caused a significant increase in plasma TMAO, which was higher after the intervention in the LC+L group than in the L (p < 0.001), and CON (p = 0.005) groups. The intervention did not change plasma TMAO concentration in the L (p = 0.959) and CON (p = 0.866) groups. After the intervention serum decorin level was higher than before in both supplemented groups combined (p = 0.012), still not significantly different to post intervention CON (p = 0.231). No changes in serum IGF-1 and myostatin concentrations and no links between the changes in blood markers and muscle function or muscle volume were observed. CONCLUSIONS: LC combined with leucine or leucine alone does not appear to improve the effectiveness of RET.


Assuntos
Carnitina , Leucina , Treinamento de Força , Feminino , Humanos , Carnitina/farmacologia , Decorina/metabolismo , Suplementos Nutricionais , Fator de Crescimento Insulin-Like I , Leucina/farmacologia , Força Muscular/fisiologia , Músculo Esquelético , Miostatina/metabolismo , Tartaratos/farmacologia , Pessoa de Meia-Idade , Idoso
10.
Genes (Basel) ; 13(10)2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36292721

RESUMO

Myostatin (MSTN), a member of the transforming growth factor-ß superfamily, inhibits the activation of muscle satellite cells. However, the role and regulatory network of MSTN in equine muscle cells are not well understood yet. We discovered that MSTN knockdown significantly reduces the proliferation rate of equine muscle satellite cells. In addition, after the RNA sequencing of equine satellite cells transfected with MSTN-interference plasmid and control plasmid, an analysis of the differentially expressed genes was carried out. It was revealed that MSTN regulatory networks mainly involve genes related to muscle function and cell-cycle regulation, and signaling pathways, such as Notch, MAPK, and WNT. Subsequent real-time PCR in equine satellite cells and immunohistochemistry on newborn and adult muscle also verified the MSTN regulatory network found in RNA sequencing analysis. The results of this study provide new insight into the regulatory mechanism of equine MSTN.


Assuntos
MicroRNAs , Miostatina , Cavalos/genética , Animais , Miostatina/genética , Miostatina/metabolismo , MicroRNAs/genética , Mioblastos/metabolismo , Músculos/metabolismo , Fatores de Crescimento Transformadores
11.
Fish Physiol Biochem ; 48(5): 1365-1375, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36125598

RESUMO

The phenomenon of sexual size dimorphism (SSD), existing in mammals, birds, reptiles, spiders, amphibians, insects, and fishes, is generally related to feeding efficiency, energy allocation, sex steroids, and somatotropic and reproductive endocrine axes. Recently, positive and negative regulations of sex steroids have been reported on SSD in various species. Chinese tongue soles (Cynoglossus semilaevis) at 4 months were fed with 17ß-estradiol (E2) and testosterone (T) supplemented feeds for 8 months to assess the effect of sex steroids on growth traits in different sexes. The potential genetic regulation was examined using several growth-related genes. The results showed that two sex steroid hormones had inhibitory effects on the growth performance of different sexes of C. semilaevis. At the age of 8 months, the expression of insulin-like growth factor 2 gene (igf2), 24-dehydrocholesterol reductase (dhcr24), leptin, and estrogen receptor 2 (esr2) in the liver showed an overall downward trend. The expression of insulin-like growth factor 1 (igf1) was reduced, while thyroid hormone receptor-associated protein 3 (thrap3) expression tended to increase in the gonad after T and E2 treatments. In the brain, somatostatin 1, tandem duplicate 2 (sst1.2) expression increased with the treatment of T and E2 (P < 0.05), while growth hormone-releasing hormone (ghrh) expression decreased. E2 and T had different effects on growth differentiation factor 8 (gdf8) and insulin-like growth factor-binding protein 7 (igfbp7) expression in the muscle. Expression of gdf8 increased in the treated fishes in contrast to the reduction expression of igfbp7. This study provided important clues for understanding the role of sex steroids in flatfish SSD.


Assuntos
Linguados , Linguado , Animais , Estradiol/metabolismo , Testosterona/metabolismo , Fator de Crescimento Insulin-Like I/genética , Leptina/metabolismo , Miostatina/metabolismo , Receptor beta de Estrogênio/metabolismo , Desmosterol/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Linguado/metabolismo , Hormônio Liberador de Hormônio do Crescimento , Peixes/metabolismo , Língua/metabolismo , Somatostatina , Receptores dos Hormônios Tireóideos , Oxirredutases/metabolismo , Linguados/genética , Mamíferos/metabolismo
12.
Clin Pharmacol Ther ; 112(6): 1291-1302, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36104012

RESUMO

Myostatin, a negative regulator of skeletal muscle growth, is a therapeutic target in muscle-wasting diseases. Domagrozumab, a humanized recombinant monoclonal antibody, binds myostatin and inhibits activity. Domagrozumab was investigated in a phase II trial (NCT02310763) as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling is vital in clinical trial design, particularly for determining dosing regimens in pediatric populations. This analysis sought to establish the PK/PD relationship between free domagrozumab and total myostatin concentrations in pediatric patients with DMD using a prior semimechanistic model developed from a phase I study in healthy adult volunteers (NCT01616277) and following inclusion of phase II data. The refined model was developed using a multiple-step approach comprising structural, random effects, and covariate model development; assessment of model adequacy (goodness-of-fit); and predictive performance. Differences in PKs/PDs between healthy adult volunteers and pediatric patients with DMD were quantitatively accounted for and evaluated by predicting myostatin coverage (the percentage of myostatin bound by domagrozumab). The final model parameter estimates and semimechanistic target-mediated drug disposition structure sufficiently described both domagrozumab and myostatin concentrations in pediatric patients with DMD, and most population parameters were comparable with the prior model (in healthy adult volunteers). Predicted myostatin coverage for phase II patients with DMD was consistently > 90%. Baseline serum myostatin was ~ 65% lower than in healthy adult volunteers. This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. Clinicaltrials.gov identifiers: NCT01616277 and NCT02310763.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Criança , Adulto , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Miostatina/metabolismo , Miostatina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Voluntários Saudáveis , Músculo Esquelético/metabolismo
13.
Ann N Y Acad Sci ; 1517(1): 203-212, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36072988

RESUMO

Citrate is an indispensable component of bone. Reduced levels of citrate in bone and serum are reported in the elderly and in osteoporosis patients. Myostatin (Mstn) is implicated in skeletal homeostasis, but its effects on osteogenesis remain incompletely understood. Nox4 has critical roles in bone homeostasis. TGF-ß/Mstn-associated Smad2/3 signaling has been linked to Nox4 expression. Insulin-like growth factor (IGF-1) has been shown to counteract many regulatory effects of Mstn. However, the crosstalk among Mstn, IGF-1, and Nox4 is not well understood; the interactive effects of those factors on citrate secretion, osteogenic differentiation, and bone remodeling remain unclear. In this study, we demonstrated that osteogenic differentiation induced an IGF-1-dependent upregulation of citrate secretion that was suppressed by Mstn. Inhibition of Nox4 prevented Mstn-induced reduction of citrate secretion. In addition, Mstn reduced bone nodule formation; these changes were prevented by Nox4 inhibition. Moreover, Mstn increased the ratio of RANKL to OPG mRNAs to favor osteoclast activation. These results indicate that Mstn negatively regulates osteogenesis by increasing levels of Nox4, which reduced IGF-1 expression, citrate secretion, and bone mineralization while also altering the RANKL to OPG ratio. These findings provide new and highly relevant insights into the osseous effects of myostatin.


Assuntos
Células-Tronco Mesenquimais , Miostatina , Camundongos , Animais , Miostatina/metabolismo , Miostatina/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Osteogênese , NADP/metabolismo , Células-Tronco Mesenquimais/metabolismo , Citratos/metabolismo , Oxirredutases/metabolismo , Músculo Esquelético/metabolismo
14.
Cells ; 11(18)2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36139428

RESUMO

Muscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron regulation mechanism. Although the detrimental effects of iron overload or iron deficiency on muscle function have been studied, the molecular mechanism of iron-dependent muscle atrophy has not been elucidated. Using human muscle tissues and in the mouse rotator cuff tear model, we confirmed an association between injury-induced iron depletion in myocytes and muscle atrophy. In differentiated C2C12 myotubes, the effects of iron deficiency on myocytes and the molecular mechanism of muscle atrophy by iron deficiency were evaluated. Our study revealed that the lower iron concentration in injured muscle was associated with the upregulation of ferroportin, an iron exporter that transports iron out of cells. Ferroportin expression was increased by hypoxia-inducible factor 1α (HIF1α), which is activated by muscle injury, and its expression is controlled by HIF1 inhibitor treatment. Iron deprivation caused myocyte loss and a marked depletion of mitochondrial membrane potential leading to muscle atrophy, together with increased levels of myostatin, the upstream regulator of atrogin1 and muscle RING-finger protein-1 (MuRF1). Myostatin expression under iron deficiency was mediated by an orphan nuclear receptor, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome (DAX1).


Assuntos
Deficiências de Ferro , Miostatina , Receptores Nucleares Órfãos , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Ferro , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/patologia , Miostatina/metabolismo , Receptores Nucleares Órfãos/metabolismo
15.
Probl Endokrinol (Mosk) ; 68(4): 102-110, 2022 Jul 24.
Artigo em Russo | MEDLINE | ID: mdl-36104971

RESUMO

BACKGROUND: Myokines are synthesized by myocytes and released into the bloodstream in response to muscle fiber contraction. They have a positive effect on carbohydrate and lipid metabolism, muscle mass growth, osteogenesis, increase tissue sensitivity to insulin, counteract inflammation of adipose tissue. The study of their secretion in response to physical activity (FA) can help to personalize the therapy of obesity. AIM: to study the features of the secretion of myokines in children with constitutionally exogenous obesity during physical activity of different duration and intensity and to evaluate their relationship with the parameters of the body composition. MATERIALS AND METHODS: 26 children (10 boys and 16 girls) were included in the study 15 [13; 16] years old, SDS BMI: +2.91 [2.24; 3.29], with sexual development according to Tanner 4-5. Two groups of 13 people were formed by random distribution. Group I performed FA (walking on a treadmill under the control of heart rate) of different duration: 30 and 60 minutes at the same intensity (less than 3 metabolic equivalents (MET)). Group II - FA of different intensity: low - less than 3 METH and moderate - 3-6 METH with the same duration of 45 minutes. Commercial kits for enzyme immunoassay were used to determine the level of myokines. The assessment of the compositional composition of the body was carried out by bioimpedance analysis (analyzer In Body 770, South Korea) in the morning, on an empty stomach. Statistical processing was carried out using STATISTICA v.12.0 (StatSoftInc., USA). The results are presented in the form of median (Me) and quartiles (Q1; Q3) corresponding to 25 and 75 percentiles. The critical significance level (p) was assumed to be <0.05. RESULTS: moderate intensity FA leads to a maximum increase in the level of myokines: interleukin-6 (IL-6) by 215.7% and decorin by 34.3%, a decrease in the level of irisin by 16.5%. An hour-long low-intensity workout leads to a moderate increase in the level of IL-6 by 80.5%, to a decrease in the level of irisin by 31.1%. Myostatin increases equally both after 60-minute FA and after moderate intensity FA by 30.9% and 31.8%, respectively. Short low-intensity FA (lasting 30 minutes) it is not accompanied by a significant increase in the expression of myokines. The relationship between the amount of muscle (r=0.65), lean (r=0.62), fat-free mass (r=0.64) and the level of decorin after FA was noted. There was no statistically significant relationship between the parameters of the body composition and the levels of IL-6, myostatin, and irisin. There were no gender differences in both basal and stimulated myokine secretion. CONCLUSION: Moderate intensity FA and low intensity 60-minute FA are most effective for obese children. A 30-minute low-intensity FN is insufficient to increase the secretion of myokines by skeletal muscles.


Assuntos
Miostatina , Obesidade Pediátrica , Adolescente , Criança , Decorina , Exercício Físico/fisiologia , Feminino , Fibronectinas/metabolismo , Humanos , Interleucina-6/metabolismo , Masculino , Miostatina/metabolismo , Obesidade Pediátrica/terapia
16.
J Trace Elem Med Biol ; 74: 127076, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36126543

RESUMO

BACKGROUND: The pollution and climate change in aquatic ecosystems are major problems threatening the aquatic organisms for existence in the recent timeline, which promotes the extinction of the fish species. However, the present study dealt with zinc nanoparticles (Zn-NPs) in mitigating arsenic, ammonia and high temperature stresses in Pangasianodon hypophthalmus. MATERIALS AND METHODS: To studying different gene expressions, an experiment was conducted to mitigate the multiple stressors using dietary Zn-NPs at 0, 2, 4, and 6 mg kg-1 diets. In the present investigation, the gene expressions studies were performed for growth hormone regulator 1 (GHR1), growth hormone regulator ß (GHRß), growth hormone (GR) in liver and gill tissue as well as myostatin (MYST) and somatostatin (SMT) in the muscle tissue. The anti-oxidative genes CAT, SOD and GPx in liver and gill tissues were also analysed. Expression studies for stress responsive heat shock protein gene (HSP70), DNA damage inducible protein, inducible nitric oxide synthase (iNOS), immune related genes such as interleukin (IL), tumour necrosis factor (TNFα), toll like receptor (TLR) and immunoglobulin were performed. At the end of the experiment the fish were infected with Aeromonas hydrophila to evaluate the immunomodulatory role of Zn-NPs. RESULTS: In the present investigation, the growth hormone regulator 1 (GHR1), growth hormone regulator ß (GHRß), growth hormone (GR) in liver and gill as well as myostatin (MYST) and somatostatin (SMT) in muscle were noticeably altered, whereas, Zn-NPs at 4 mg kg-1 diet improved gene expressions. The anti-oxidant gene viz. CAT, SOD and GPx in liver and gill tissues were upregulated by stressors such as As, NH3, NH3+T. As+T and As+NH3+T. Therefore, anti-oxidant genes were noticeably improved with dietary Zn-NPs diet. The stress protein gene (HSP70), DNA damage inducible protein, inducible nitric oxide synthase (iNOS) was significantly upregulated, whereas, Zn-NPs diet was applied to the corrected gene regulation. Similarly, immune related genes such as interleukin (IL), tumour necrosis factor (TNFα), toll like receptor (TLR) and immunoglobulin were highly affected by stressors. Dietary Zn-NPs at 4 mg kg-1 diet was improved all the immune related gene expression and mitigate arsenic, ammonia and high temperature stress in fish. CONCLUSION: The present investigation revealed that Zn-NPs at 4.0 mg kg-1 diet has enormous potential to modulates arsenic, ammonia and high temperature stress, and protect against pathogenic infections in fish.


Assuntos
Arsênio , Peixes-Gato , Nanopartículas Metálicas , Amônia , Ração Animal/análise , Animais , Antioxidantes/metabolismo , Arsênio/metabolismo , Dieta , Suplementos Nutricionais/análise , Ecossistema , Hormônio do Crescimento/metabolismo , Proteínas de Choque Térmico/metabolismo , Miostatina/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Somatostatina/metabolismo , Superóxido Dismutase/metabolismo , Temperatura , Fator de Necrose Tumoral alfa/metabolismo , Zinco/metabolismo , Zinco/farmacologia
17.
Endocrinol Metab (Seoul) ; 37(4): 684-697, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36065648

RESUMO

BACKGRUOUND: Muscle atrophy is caused by an imbalance between muscle growth and wasting. Delta-like 1 homolog (DLK1), a protein that modulates adipogenesis and muscle development, is a crucial regulator of myogenic programming. Thus, we investigated the effect of exogenous DLK1 on muscular atrophy. METHODS: We used muscular atrophy mouse model induced by dexamethasone (Dex). The mice were randomly divided into three groups: (1) control group, (2) Dex-induced muscle atrophy group, and (3) Dex-induced muscle atrophy group treated with DLK1. The effects of DLK1 were also investigated in an in vitro model using C2C12 myotubes. RESULTS: Dex-induced muscular atrophy in mice was associated with increased expression of muscle atrophy markers and decreased expression of muscle differentiation markers, while DLK1 treatment attenuated these degenerative changes together with reduced expression of the muscle growth inhibitor, myostatin. In addition, electron microscopy revealed that DLK1 treatment improved mitochondrial dynamics in the Dex-induced atrophy model. In the in vitro model of muscle atrophy, normalized expression of muscle differentiation markers by DLK1 treatment was mitigated by myostatin knockdown, implying that DLK1 attenuates muscle atrophy through the myostatin pathway. CONCLUSION: DLK1 treatment inhibited muscular atrophy by suppressing myostatin-driven signaling and improving mitochondrial biogenesis. Thus, DLK1 might be a promising candidate to treat sarcopenia, characterized by muscle atrophy and degeneration.


Assuntos
Miostatina , Sarcopenia , Animais , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Miostatina/metabolismo , Miostatina/farmacologia , Sarcopenia/metabolismo , Transdução de Sinais
18.
Am J Physiol Cell Physiol ; 323(5): C1402-C1409, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36094432

RESUMO

Skeletal muscle mass is negatively regulated by several TGF-ß superfamily members. Myostatin (MSTN) is the most prominent negative regulator of muscle mass. Recent studies show that in addition to MSTN, GDF11, which shares a high sequence identity with MSTN, induces muscle atrophy in vitro and in vivo at supraphysiological levels, whereas controversy regarding its roles exists. Furthermore, higher circulating GDF11 levels associate with frailty in humans. On the other hand, little is known about the effect of pathophysiological levels of GDF11 on muscle atrophy. Here we seek to determine whether pathophysiological levels of GDF11 are sufficient to activate Smad2/Smad3 signaling and induce muscle atrophy using human iPSC-derived myocytes (hiPSC myocytes). We first show that incubating hiPSC myocytes with pathophysiological concentrations of GDF11 significantly reduces myocyte diameters. We next demonstrate that pathophysiological levels of GDF11 are sufficient to activate Smad2/3 signaling. Finally, we show that pathophysiological levels of GDF11 are capable of inducing the expression of Atrogin-1, an atrophy-promoting E3 ubiquitin ligase and that FOXO1 blockage reverses the GDF11-induced Atrogin-1 expression and atrophic phenotype. Collectively, our results suggest that GDF11 induces skeletal muscle atrophy at the pathophysiological levels through the GDF11-FOXO1 axis.


Assuntos
Células-Tronco Pluripotentes Induzidas , Miostatina , Humanos , Miostatina/genética , Miostatina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Atrofia Muscular/patologia , Músculo Esquelético/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Musculares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína Smad3/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Proteína Smad2/genética
19.
Res Vet Sci ; 152: 228-235, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36027840

RESUMO

Current studies on myostatin (MSTN), a well-known negative regulator of skeletal muscle, studies mainly focus on the its effects on skeletal muscle.However, its effects on smooth muscle are less studied, especially in the uterine horns. To identify the role of MSTN in uterine horn smooth muscle, this study used 6-8-month-old homozygous MSTN mutant (MSTN-/-) gilts in anoestrum as animal models. Histochemical and immunofluorescence staining, western blotting, and RT-qPCR were performed. The results showed that the uteri of the MSTN-/- gilts were morphologically normal, and the uterine horn smooth muscle content was increased (MSTN-/-: 75.19%, Wild type: 51.52%, P < 0.01). In vivo immunofluorescence staining showed that the expression of the uterine horn smooth muscle-specific marker proteins, namely α-smooth muscle actin (ACTA2) and calponin, increased after MSTN knockout (1.41- and 1.21-fold, respectively, P < 0.05). Increased gene expression was also seen in MSTN-/- gilts in vivo for ACTA2 (approximately 2-fold), smooth muscle myosin heavy chain (7.14-fold), myocardin (9.32-fold), and serum response factor (2.17-fold). Protein expression of smooth muscle-specific markers was increased (1.51-fold for ACTA2, 1.57-fold for calponin, P<0.05). MSTN knockout promoted proliferation of the smooth muscle cell and the gene expression of c-kit, a peristaltic marker (2.43-fold, P < 0.05). The results of the in vitro experiments were consistent with those of the in vivo experiments. The present study indicates that MSTN knockout can increase the smooth muscle content of uterine horns, thus providing potential therapeutic targets for pregnancy disorders caused by increased smooth muscle content.


Assuntos
Músculo Esquelético , Miostatina , Animais , Suínos , Feminino , Miostatina/genética , Miostatina/metabolismo , Músculo Esquelético/fisiologia , Sus scrofa , Músculo Liso , Útero
20.
Sheng Wu Gong Cheng Xue Bao ; 38(8): 3076-3089, 2022 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-36002433

RESUMO

Myostatin (Mstn) is known as growth/differentiation factor-8 (GDF-8). Knockout or knockdown of Mstn gene promotes muscle development and reduces fat content. Here we prepared Mstn knockdown mice by RNA interference, then the morphology of the skeletal muscle, the content of triglyceride (TG), the content and composition of fatty acids in the skeletal muscle were detected. The expression of Mstn reduced in muscle of Mstn knockdown mice compared to the controls. The cross sectional areas of the skeletal muscle myofibers were significantly larger while the content of TG was less than that of the controls, and the ratios of n-3/n-6 and unsat/sat in the knockdown mice increased significantly. Subsequently, we detected the expression of genes associated with fatty acid metabolism. The expression of the genes associated with lipolysis and fatty acid transportation were up-regulated, while the genes associated with fatty acid synthesis were down-regulated. Of these genes, the up-regulation of a gene associated with ß oxidation, Cpt1b, was up-regulated remarkably. We further detected the enzyme activity of CPT1 in skeletal muscle and obtained the same results with gene expression. Moreover, chromatin immunoprecipitation assay was performed and we found that SMAD3, a transcription factor downstream of Mstn, directly binds to the promoter of Cpt1b gene. These results showed that knockdown of Mstn up-regulated the expression of Cpt1b through the binding of SMAD3 to the promoter of Cpt1b, then promoted the ß oxidation metabolism of intramuscular fatty acids.


Assuntos
Metabolismo dos Lipídeos , Miostatina , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo , Miostatina/genética , Miostatina/metabolismo , Oxirredução , Regulação para Cima
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