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1.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360594

RESUMO

Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11ß-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11ß-HSD1 activity ex vivo. Using the TNF-α-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11ß-HSD1 global knock-out (11ßKO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11ß-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg11ßKO mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg11ßKO mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg11ßKO compared to TNF-tg mice. In summary, 11ß-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11ß-HSD1 may offer a strategy to refine the safety of glucocorticoids.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Artrite Reumatoide/tratamento farmacológico , Deleção de Genes , Glucocorticoides/efeitos adversos , Atrofia Muscular/prevenção & controle , Osteoartrite do Quadril/tratamento farmacológico , Animais , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Atrofia Muscular/patologia , Osteoartrite do Quadril/patologia
2.
Nutrients ; 13(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34371902

RESUMO

There is ongoing debate as to whether or not α-hydroxyisocaproic acid (HICA) positively regulates skeletal muscle protein synthesis resulting in the gain or maintenance of skeletal muscle. We investigated the effects of HICA on mouse C2C12 myotubes under normal conditions and during cachexia induced by co-exposure to TNFα and IFNγ. The phosphorylation of AMPK or ERK1/2 was significantly altered 30 min after HICA treatment under normal conditions. The basal protein synthesis rates measured by a deuterium-labeling method were significantly lowered by the HICA treatment under normal and cachexic conditions. Conversely, myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by the HICA pretreatment, and this improvement was accompanied by the inhibition of iNOS expression and IL-6 production. Moreover, HICA also suppressed the TNFα/IFNγ co-exposure-induced secretion of 3-methylhistidine. These results demonstrated that HICA decreases basal protein synthesis under normal or cachexic conditions; however, HICA might attenuate skeletal muscle atrophy via maintaining a low level of protein degradation under cachexic conditions.


Assuntos
Caquexia/tratamento farmacológico , Caproatos/farmacologia , Interferon gama/toxicidade , Interleucina-6/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Caquexia/induzido quimicamente , Caquexia/metabolismo , Caquexia/patologia , Linhagem Celular , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Metilistidinas/metabolismo , Camundongos , Fibras Musculares Esqueléticas/enzimologia , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Fosforilação , Biossíntese de Proteínas , Proteólise
3.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360821

RESUMO

Dexamethasone (Dexa), frequently used as an anti-inflammatory agent, paradoxically leads to muscle inflammation and muscle atrophy. Receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) lead to nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome formation through nuclear factor-κB (NF-κB) upregulation. NLRP3 inflammasome results in pyroptosis and is associated with the Murf-1 and atrogin-1 upregulation involved in protein degradation and muscle atrophy. The effects of Ecklonia cava extract (ECE) and dieckol (DK) on attenuating Dexa-induced muscle atrophy were evaluated by decreasing NLRP3 inflammasome formation in the muscles of Dexa-treated animals. The binding of AGE or high mobility group protein 1 to RAGE or TLR4 was increased by Dexa but significantly decreased by ECE or DK. The downstream signaling pathways of RAGE (c-Jun N-terminal kinase or p38) were increased by Dexa but decreased by ECE or DK. NF-κB, downstream of RAGE or TLR4, was increased by Dexa but decreased by ECE or DK. The NLRP3 inflammasome component (NLRP3 and apoptosis-associated speck-like), cleaved caspase -1, and cleaved gasdermin D, markers of pyroptosis, were increased by Dexa but decreased by ECE and DK. Interleukin-1ß/Murf-1/atrogin-1 expression was increased by Dexa but restored by ECE or DK. The mean muscle fiber cross-sectional area and grip strength were decreased by Dexa but restored by ECE or DK. In conclusion, ECE or DK attenuated Dexa-induced muscle atrophy by decreasing NLRP3 inflammasome formation and pyroptosis.


Assuntos
Benzofuranos/farmacologia , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Inflamassomos/efeitos dos fármacos , Atrofia Muscular , Piroptose/efeitos dos fármacos , Animais , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Extratos Vegetais/farmacologia
4.
Int J Chron Obstruct Pulmon Dis ; 16: 1661-1675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113097

RESUMO

Background: Exposure to cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD). CS not only causes chronic airway inflammation and lung damage but also is involved in skeletal muscle dysfunction (SMD). Previous studies have shown that histone deacetylase 2 (HDAC2) plays an important role in the progression of COPD. The aim of this study was to determine the role of HDAC2 in CS-induced skeletal muscle atrophy and senescence. Methods: Gastrocnemius muscle weight and cross-sectional area (CSA) were measured in mice with CS-induced emphysema, and changes in the expression of atrophy-related markers and senescence-related markers were detected. In addition, the relationship between HDAC2 expression and skeletal muscle atrophy and senescence was also investigated. Results: Mice exposed to CS for 24 weeks developed emphysema and gastrocnemius atrophy and exhibited a decrease in gastrocnemius weight and skeletal muscle cross-sectional area. In addition, the HDAC2 protein levels were significantly decreased while the levels of atrophy-associated markers, including MURF1 and MAFbx, and senescence-associated markers, including P53 and P21, were significantly increased in the gastrocnemius muscle. In vitro, the exposure of C2C12 cells to cigarette smoke extract (CSE) significantly increased the MAFbx and MURF1 protein levels and decreased the HDAC2 protein levels. Moreover, overexpression of HDAC2 significantly ameliorated CSE-induced atrophy and senescence and reversed the increased MURF1, MAFbx, P53, and P21 expression in C2C12 cells. In addition, CSE treatment significantly increased the IKK and NF-κB p65 protein levels, and PTDC (an NF-kB inhibitor) ameliorated atrophy and senescence. Conclusion: Our findings suggest that HDAC2 plays an important role in CS-induced skeletal muscle atrophy and senescence, possibly through the NF-κB pathway.


Assuntos
Enfisema , Doença Pulmonar Obstrutiva Crônica , Animais , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/prevenção & controle , NF-kappa B/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Transdução de Sinais , Fumaça/efeitos adversos , Fumar/efeitos adversos
5.
Medicina (Kaunas) ; 57(5)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066110

RESUMO

Background and Objectives: The present study investigated the beneficial effects of tart cherry (fruit of Prunus cerasus) concentrated powder (TCcp) on glucocorticoid (GLU)-induced catabolic muscular atrophy in the skeletal muscle of mice. Furthermore, its potential mechanism was also studied. Materials and Methods: Changes in calf thickness, calf muscle weight, calf muscle strength, body weight, gastrocnemius muscle histology, immunohistochemistry, serum creatinine, creatine kinase, lactate dehydrogenase, and antioxidant defense systems were measured. Malondialdehyde, reactive oxygen species, glutathione content, catalase, and superoxide dismutase activities in the gastrocnemius muscle, and muscle-specific mRNA expressions were evaluated. Results: After 24 days, GLU control mice showed muscular atrophy at all criteria of indexes. The muscular atrophy symptoms were significantly inhibited by oral treatment with 250 mg/kg and 500 mg/kg of TCcp through antioxidative and anti-inflammatory modulated expression of genes involved in muscle protein degradation (myostatin, atrogin-1, SIRT1, and MuRF1) and synthesis (A1R, Akt1, TRPV4, and PI3K). Conclusions: This study shows that the TCcp (500 mg/kg and 250 mg/kg) could improve muscular atrophies caused by various etiologies.


Assuntos
Frutas , Prunus avium , Animais , Glucocorticoides , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/patologia , Pós , Canais de Cátion TRPV
6.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33955507

RESUMO

The protein extracted from red algae Pyropia yezoensis has various biological activities, including anti­inflammatory, anticancer, antioxidant, and antiobesity properties. However, the effects of P. yezoensis protein (PYCP) on tumor necrosis factor­α (TNF­α)­induced muscle atrophy are unknown. Therefore, the present study investigated the protective effects and related mechanisms of PYCP against TNF­α­induced myotube atrophy in C2C12 myotubes. Treatment with TNF­α (20 ng/ml) for 48 h significantly reduced myotube viability and diameter and increased intracellular reactive oxygen species levels; these effects were significantly reversed in a dose­dependent manner following treatment with 25­100 µg/ml PYCP. PYCP inhibited the expression of TNF receptor­1 in TNF­α­induced myotubes. In addition, PYCP markedly downregulated the nuclear translocation of nuclear factor­κB (NF­κB) by inhibiting the phosphorylation of inhibitor of κB. Furthermore, PYCP treatment suppressed 20S proteasome activity, IL­6 production, and the expression of the E3 ubiquitin ligases, atrogin­1/muscle atrophy F­box and muscle RING­finger protein­1. Finally, PYCP treatment increased the protein expression levels of myoblast determination protein 1 and myogenin in TNF­α­induced myotubes. The present findings indicate that PYCP may protect against TNF­α­induced myotube atrophy by inhibiting the proinflammatory NF­κB pathway.


Assuntos
Proteínas de Algas/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Substâncias Protetoras/farmacologia , Rodófitas/química , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Camundongos , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Proteína MyoD/metabolismo , Miogenina/metabolismo , NF-kappa B/metabolismo , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
7.
Phytother Res ; 35(8): 4363-4376, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33876509

RESUMO

Cisplatin (DDP) is widely used in cancer treatment, but DDP can cause skeletal muscle atrophy and cachexia. This study explored the effect and mechanism of daidzein (DAI) in reducing DDP-induced skeletal muscle atrophy and cachexia in vivo and in vitro. DAI alleviated the weight, food intake, muscle, adipose tissue, kidney weight and forelimb grip of LLC tumour-bearing mice after DDP treatment, and did not affect the antitumour effect of DDP. DAI can reduce the decrease of the cross-sectional area of skeletal muscle fibre-induced by DDP and prevent the change of fibre type proportion. In skeletal muscle, it can inhibit Glut4/AMPK/FoxO pathway, down-regulate the expression of atrogin1 and MuRF1, and inhibit skeletal muscle protein degradation. In DDP treated C2C12 myotubes, DAI could inhibit Glut4/AMPK/FoxO pathway to reduce myotubes atrophy, while AMPK agonist MK-3903 could reverse the protective effect of DAI. These results suggest that DAI can alleviate DDP-induced skeletal muscle atrophy by downregulating the expression of Atrogin1 and MuRF1 through the regulation of Glut4/AMPK/FoxO pathway.


Assuntos
Cisplatino , Isoflavonas/uso terapêutico , Atrofia Muscular , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP , Animais , Cisplatino/efeitos adversos , Proteína Forkhead Box O1 , Transportador de Glucose Tipo 4 , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Proteínas Quinases , Proteínas Ligases SKP Culina F-Box , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
8.
Arch Biochem Biophys ; 704: 108873, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33848514

RESUMO

Glucocorticoids are the drugs most commonly used to manage inflammatory diseases. However, they are prone to inducing muscle atrophy by increasing muscle proteolysis and decreasing protein synthesis. Various studies have demonstrated that antioxidants can mitigate glucocorticoid-induced skeletal muscle atrophy. Here, we investigated the effect of a potent antioxidative natural flavonoid, morin, on the muscle atrophy and oxidative stress induced by dexamethasone (Dex) using mouse C2C12 skeletal myotubes. Dex (10 µM) enhanced the production of reactive oxygen species (ROS) in C2C12 myotubes via glucocorticoid receptor. Moreover, Dex administration reduced the diameter and expression levels of the myosin heavy chain protein in C2C12 myotubes, together with the upregulation of muscle atrophy-associated ubiquitin ligases, such as muscle atrophy F-box protein 1/atrogin-1, muscle ring finger protein-1, and casitas B-lineage lymphoma proto-oncogene-b. Dex also significantly decreased phosphorylated Foxo3a and increased total Foxo3a expression. Interestingly, Dex-induced ROS accumulation and Foxo3a expression were inhibited by morin (10 µM) pretreatment. Morin also prevented the Dex-induced reduction of myotube thickness, together with muscle protein degradation and suppression of the upregulation of atrophy-associated ubiquitin ligases. In conclusion, our results suggest that morin effectively prevents glucocorticoid-induced muscle atrophy by reducing oxidative stress.


Assuntos
Dexametasona , Flavonoides/farmacologia , Fibras Musculares Esqueléticas , Proteínas Musculares/metabolismo , Atrofia Muscular , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular , Dexametasona/efeitos adversos , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-33804338

RESUMO

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.


Assuntos
Dexametasona , Fibras Musculares Esqueléticas , Dexametasona/toxicidade , Humanos , Mitocôndrias , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , Regulação para Cima
10.
Nutrients ; 13(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810214

RESUMO

Fucoxanthin (Fx) has preventive effect against muscle atrophy and myotube loss in vitro, but it has not yet been examined in vivo. Therefore, we aimed to investigate the effect of Fx on dexamethasone (Dex)-induced muscle atrophy and fat mass in mice. ICR mice were fed with Fx diets from 2 weeks before Dex treatment to the end of the study. Muscle atrophy was induced in the mice by oral administration of Dex. Body weight was significantly lower by Dex treatment. Visceral fat mass in the Fx-treated group were significantly lower than those in the control group. The Dex-induced decrease in tibialis anterior muscle mass was ameliorated by Fx treatment. Fx treatment significantly attenuated muscle lipid peroxidation compared with the control and Dex-treated groups. The phosphorylation of AMPK was significantly higher in the Dex-treated group than in the control group. The expression of cytochrome c oxidase (COX) IV was significantly higher in the Fx-treated group than in the control group. These results suggest that Fx may be a beneficial material to prevent muscle atrophy in vivo, in addition to the effect of fat loss.


Assuntos
Dexametasona/toxicidade , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/prevenção & controle , Xantofilas/uso terapêutico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Musculares/genética , Proteínas Musculares/metabolismo
11.
Nutrients ; 13(3)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799389

RESUMO

(1) The study aimed to investigate whether vitamin D3 supplementation would positively affect rats with glucocorticoids-induced muscle atrophy as measured by skeletal muscle mass in two experimental conditions: chronic dexamethasone (DEX) administration and a model of the chronic stress response. (2) The study lasted 28 consecutive days and was performed on 45 male Wistar rats randomly divided into six groups. These included two groups treated by abdominal injection of DEX at a dose of 2 mg/kg/day supplemented with vegetable oil (DEX PL; n = 7) or with vitamin D3 600 IU/kg/day (DEX SUP; n = 8), respectively, and a control group treated with an abdominal injection of saline (CON; n = 6). In addition, there were two groups of rats chronically stressed by cold water immersion (1 hour/day in a glass box with 1-cm-deep ice/water mixture; temperature ~4 °C), which were supplemented with vegetable oil as a placebo (STR PL; n = 9) or vitamin D3 at 600 IU/kg/day (STR SUP; n = 9). The last group was of sham-stressed rats (SHM; n = 6). Blood, soleus, extensor digitorum longus, gastrocnemius, tibialis anterior, and quadriceps femoris muscles were collected and weighed. The heart, liver, spleen, and thymus were removed and weighed immediately after sacrifice. The plasma corticosterone (CORT) and vitamin D3 metabolites were measured. (3) We found elevated CORT levels in both cold water-immersed groups; however, they did not alter body and muscle weight. Body weight and muscle loss occurred in groups with exogenously administered DEX, with the exception of the soleus muscle in rats supplemented with vitamin D3. Decreased serum 25(OH)D3 concentrations in DEX-treated rats were observed, and the cold water immersion did not affect vitamin D3 levels. (4) Our results indicate that DEX-induced muscle loss was abolished in rats supplemented with vitamin D3, especially in the soleus muscle.


Assuntos
Colecalciferol/uso terapêutico , Glucocorticoides/administração & dosagem , Atrofia Muscular/tratamento farmacológico , Vitaminas/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Ratos , Ratos Wistar , Resultado do Tratamento , Vitamina D
12.
Br J Pharmacol ; 178(15): 2998-3016, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33788266

RESUMO

BACKGROUND AND PURPOSE: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy. EXPERIMENTAL APPROACH: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test. KEY RESULTS: Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml-1 )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1ß and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mg·kg-1 , i.p.)-challenged mice, triptolide (5 and 20 µg·kg-1 ·day-1 , i.p.) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion. CONCLUSIONS AND IMPLICATIONS: These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.


Assuntos
NF-kappa B , Fator de Necrose Tumoral alfa , Animais , Diterpenos , Compostos de Epóxi , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , Fenantrenos
13.
J Biol Chem ; 296: 100395, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33567340

RESUMO

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.


Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Glucocorticoides/farmacologia , Glucose/metabolismo , Resistência à Insulina , Músculo Estriado/efeitos dos fármacos , Músculo Estriado/metabolismo , Atrofia Muscular/metabolismo , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Estriado/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
14.
J Toxicol Sci ; 46(1): 11-24, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33408297

RESUMO

Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.


Assuntos
Fenofibrato/efeitos adversos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Lovastatina/efeitos adversos , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Animais , Atrofia , Quimioterapia Combinada/efeitos adversos , Fenofibrato/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lovastatina/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Rabdomiólise/induzido quimicamente , Rabdomiólise/genética
15.
Biomed Pharmacother ; 136: 111226, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33485066

RESUMO

Chrysanthemum zawadskii Herbich (CZH) is used in traditional medicine to treat inflammatory diseases and diabetes. However, the effects of CZH on muscle wasting remains to be studied. Here, we investigated the effect of CZH on dexamethasone (DEX), a synthetic glucocorticoid, induced muscle atrophy. To examine the effect of CZH on muscle atrophy, C2C12 myotubes were co-treated with DEX and CZH for 24 h. The treatment with CZH prevented DEX-induced myotube atrophy in a dose-dependent manner. CZH inhibited the DEX-induced decrease of the MHC isoforms and the upregulation of atrogin-1 and MuRF1 in C2C12 differentiated cells. C57BL/6 mice were supplemented with 0.1 % CZH for 8 weeks, with DEX-induced muscle atrophy stimulated in the last 3 weeks. In the mice, CZH supplementation effectively reversed DEX-induced skeletal muscle atrophy and increased the exercise capacity of the mice through the inhibition of glucocorticoid receptor translocation. Additionally, we observed that DEX-evoked impaired proteostasis was ameliorated via the Akt/mTOR pathway. CZH also prevented the DEX-induced decrease in the mitochondrial respiration. HPLC analysis demonstrated the highest concentration of acacetin-7-O-ß-d-rutinoside (AR) among 4 compounds. Moreover, AR, a functional compound of CZH, prevented DEX-evoked muscle atrophy. Thus, we suggest that CZH could be a potential therapeutic candidate against muscle atrophy and AR is the main functional compound of CZH.


Assuntos
Chrysanthemum , Flavonoides/farmacologia , Glicosídeos/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Chrysanthemum/química , Dexametasona , Modelos Animais de Doenças , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Extratos Vegetais/isolamento & purificação , Proteostase
16.
Nat Chem Biol ; 17(3): 307-316, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33510451

RESUMO

Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.


Assuntos
Anti-Inflamatórios/farmacologia , Transportador de Glucose Tipo 4/genética , Atrofia Muscular/tratamento farmacológico , Receptores de Glucocorticoides/química , Transdução de Sinais/efeitos dos fármacos , Células A549 , Regulação Alostérica , Animais , Anti-Inflamatórios/síntese química , Linhagem Celular Transformada , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Lipopolissacarídeos/administração & dosagem , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Ratos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade
17.
Nicotine Tob Res ; 23(1): 143-151, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31965191

RESUMO

INTRODUCTION: Apart from its adverse effects on the respiratory system, cigarette smoking also induces skeletal muscle atrophy and dysfunction. Whether short-term smoking cessation can restore muscle mass and function is unknown. We, therefore, studied the impact of 1- and 2-week smoking cessation on skeletal muscles in a mouse model. METHODS: Male mice were divided into four groups: Air-exposed (14 weeks); cigarette smoke (CS)-exposed (14 weeks); CS-exposed (13 weeks) followed by 1-week cessation; CS-exposed (12 weeks) followed by 2 weeks cessation to examine exercise capacity, physical activity levels, body composition, muscle function, capillarization, mitochondrial function and protein expression in the soleus, plantaris, and diaphragm muscles. RESULTS: CS-induced loss of body and muscle mass was significantly improved within 1 week of cessation due to increased lean and fat mass. Mitochondrial respiration and protein levels of the respiratory complexes in the soleus were lower in CS-exposed mice, but similar to control values after 2 weeks of cessation. Exposing isolated soleus muscles to CS extracts reduced mitochondrial respiration that was reversed after removing the extract. While physical activity was reduced in all groups, exercise capacity, limb muscle force, fatigue resistance, fiber size and capillarization, and diaphragm cytoplasmic HIF-1α were unaltered by CS-exposure. However, CS-induced diaphragm atrophy and increased capillary density were not seen after 2 weeks of smoking cessation. CONCLUSION: In male mice, 2 weeks of smoking cessation reversed smoking-induced mitochondrial dysfunction, limb muscle mass loss, and diaphragm muscle atrophy, highlighting immediate benefits of cessation on skeletal muscles. IMPLICATIONS: Our study demonstrates that CS-induced skeletal muscle mitochondrial dysfunction and atrophy are significantly improved by 2 weeks of cessation in male mice. We show for the first time that smoking cessation as short as 1 to 2 weeks is associated with immediate beneficial effects on skeletal muscle structure and function with the diaphragm being particularly sensitive to CS-exposure and cessation. This could help motivate smokers to quit smoking as early as possible. The knowledge that smoking cessation has potential positive extrapulmonary effects is particularly relevant for patients referred to rehabilitation programs and those admitted to hospitals suffering from acute or chronic muscle deterioration yet struggling with smoking cessation.


Assuntos
Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Abandono do Hábito de Fumar/métodos , Fumar/efeitos adversos , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Condicionamento Físico Animal
18.
J Ethnopharmacol ; 266: 113403, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32971160

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The dried root of Paeonia lactiflora Pall. (Radix Paeoniae) has been traditionally used to treat various inflammatory diseases in many Asian countries. AIM OF THE STUDY: Cisplatin is a broad-spectrum anticancer drug used in diverse types of cancer. However, muscle wasting is a common side effect of cisplatin chemotherapy. This study aimed to elucidate the effects of an ethanol extract of the root of Paeonia lactiflora Pall. (Radix Paeoniae, RP) on cisplatin-induced muscle wasting along with its molecular mechanism. MATERIAL AND METHODS: C57BL/6 mice were intraperitoneally injected with cisplatin and orally treated with RP. Megestrol acetate was used as a comparator drug. Skeletal muscle mass was measured as the weight of gastrocnemius and quadriceps muscles, and skeletal muscle function was measured by treadmill running time and grip strength. Skeletal muscle tissues were analyzed by RNAseq, western blotting, ELISA, and immunofluorescence microscopy. RESULTS: In mice treated with cisplatin, skeletal muscle mass and skeletal muscle function were significantly reduced. However, oral administration of RP significantly restored skeletal muscle mass and function in the cisplatin-treated mice. In the skeletal muscle tissues of the cisplatin-treated mice, RP downregulated NF-κB signaling and cytokine levels. RP also downregulated muscle-specific ubiquitin E3 ligases, resulting in the restoration of myosin heavy chain (MyHC) and myoblast determination protein (MyoD), which play crucial roles in muscle contraction and muscle differentiation, respectively. CONCLUSION: RP restored skeletal muscle function and mass in cisplatin-treated mice by restoring the muscle levels of MyHC and MyoD proteins via downregulation of muscle-specific ubiquitin E3 ligases as well as muscle NF-κB signaling and cytokine levels.


Assuntos
Cisplatino/toxicidade , Atrofia Muscular/prevenção & controle , Paeonia/química , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/toxicidade , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
19.
J Cell Physiol ; 236(1): 260-272, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32506638

RESUMO

Skeletal muscle atrophy is characterized by the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. An increase in the expression of two muscle-specific E3 ligases, atrogin-1 and MuRF-1, and oxidative stress are involved in muscle atrophy. Patients with chronic liver diseases (CLD) develop muscle wasting. Several bile acids increase in plasma during cholestatic CLD, among them, cholic acid (CA) and deoxycholic acid (DCA). The receptor for bile acids, TGR5, is expressed in healthy skeletal muscles. TGR5 is involved in the regulation of muscle differentiation and metabolic changes. In this paper, we evaluated the participation of DCA and CA in the generation of an atrophic condition in myotubes and isolated fibers from the muscle extracted from wild-type (WT) and TGR5-deficient (TGR5-/- ) male mice. The results show that DCA and CA induce a decrease in diameter, and myosin heavy chain (MHC) protein levels, two typical atrophic features in C2 C12 myotubes. We also observed similar results when INT-777 agonists activated the TGR5 receptor. To evaluate the participation of TGR5 in muscle atrophy induced by DCA and CA, we used a culture of muscle fiber isolated from WT and TGR5-/- mice. Our results show that DCA and CA decrease the fiber diameter and MHC protein levels, and there is an increase in atrogin-1, MuRF-1, and oxidative stress in WT fibers. The absence of TGR5 in fibers abolished all these effects induced by DCA and CA. Thus, we demonstrated that CS and deoxycholic acid induce skeletal muscle atrophy through TGR5 receptor.


Assuntos
Ácido Cólico/farmacologia , Ácido Desoxicólico/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Cadeias Pesadas de Miosina/efeitos dos fármacos , Cadeias Pesadas de Miosina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
Nat Commun ; 11(1): 4653, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938923

RESUMO

Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.


Assuntos
Açúcares da Dieta/efeitos adversos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Neoplasias Experimentais/fisiopatologia , Prolina/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Animais Geneticamente Modificados , Carcinogênese , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Hemolinfa/efeitos dos fármacos , Hemolinfa/metabolismo , Larva , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Neoplasias Experimentais/etiologia , Proteínas Nucleares/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transativadores/genética , Proteínas ras/genética
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