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1.
Chem Biol Interact ; 315: 108893, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31706954

RESUMO

This study aimed to investigate the effects of teaghrelin, an active ingredient of Chin-shin oolong tea, on murine C2C12 myoblast cells. Under high serum conditions, teaghrelin inhibited C2C12 cell proliferation, indicating a cell cycle arrest and cessation of proliferative progression. Teaghrelin promoted pro-differentiation of C2C12 cells as evidenced by a progressively elongated morphology, as well as the induction of muscle specific myogenin, myosin heavy chain (MHC), and MyoD. The formation of multinucleated myotubes, and the increase of MHC-positive immunoreactivity within the myotubes, further reflected a complete differentiation and maturation of the contractile skeletal muscle cells induced by teaghrelin. Like ghrelin, teaghrelin attenuated dexamethasone-decreased myotube diameter, indicating its protective effects against skeletal muscle atrophy. Additionally, the expressions of Atrogin-1 and MuRF-1 ubiquitin E3 ligase were reduced. In conclusion, the results highlight a possibility of developing teaghrelin as a functional food for the prevention or therapeutic treatment of disease-associated skeletal muscle atrophy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Grelina/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá/química , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Miogenina/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
2.
Life Sci ; 237: 116919, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610200

RESUMO

AIMS: Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly lower body weight than normotensive Wistar-Kyoto rats (WKY). Our hypotheses are as follows: weight loss of the skeletal muscle is related to hypertension-related diseases, and muscle hypotrophy is useful as a therapeutic target for hypertension and hypertension-related diseases. In this study, we aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). MAIN METHODS: The difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length, histological, gene expression, and protein expression analyses. KEY FINDINGS: SHRSP had a significantly lower weight/tibial length in soleus and gastrocnemius, but not in plantaris and tibialis anterior, indicating that muscles consisting of a relatively high amount of slow muscle fiber were affected. This result was confirmed by the histological analysis of soleus, showing that type I fiber mainly decreased the fiber size. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in soleus, but not in plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator by Ingenuity Pathway Analysis and immunostained only in type II fiber in WKY but in both type I and II fibers in SHRSP. SIGNIFICANCE: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fiber of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression.


Assuntos
Hipertensão/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Liso Vascular/patologia , Atrofia Muscular/patologia , Acidente Vascular Cerebral/patologia , Receptor de TWEAK/metabolismo , Animais , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Receptor de TWEAK/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
3.
BMC Complement Altern Med ; 19(1): 267, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615487

RESUMO

BACKGROUND: Cancer cachexia is a cancer-induced multifactorial debilitating syndrome directly accounting for 20% of cancer deaths without effective therapeutic approaches. It is extremely urgent to explore effective anti-cachexia drugs to ameliorate muscle and fat loss in cachexia patients. METHODS: Lewis lung carcinoma bearing C57BL/6 mice were applied as the animal model to examine the therapeutic effect of Coix seed oil (CSO) on cancer cachexia. The food intake and body weight change were monitored every 3 days throughout the experiment. The IL-6 and TNF-α levels in serum were detected by ELISA assay. Several key proteins involved in muscle wasting and fat lipolysis were tested by Western blot to identify the potential mechanism of CSO. RESULTS: Administration of CSO through gavage significantly prevented body weight loss and ameliorated systemic inflammation without affecting food intake and tumor size. The weight and histological morphology of gastrocnemius muscle and epididymal adipose tissue in CSO-treated mice were also improved. In mechanism, we found that CSO decreased the expression of MuRF1 and the ratio of phospho-p65 (Ser536) to p65 in muscle tissue. Meanwhile, cancer-induced activation of HSL and AMPK was also inhibited by CSO administration. CONCLUSION: Coix seed oil exerts an anti-cachexia pharmaceutical effect by counteracting muscle and adipose tissue loss most likely through regulating NF-κB-MuRF1 and AMPK-HSL pathway.


Assuntos
Tecido Adiposo/metabolismo , Caquexia/tratamento farmacológico , Coix/química , Lipólise/efeitos dos fármacos , Neoplasias Pulmonares/complicações , Atrofia Muscular/tratamento farmacológico , Óleos Vegetais/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/fisiopatologia , Feminino , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , NF-kappa B/genética , NF-kappa B/metabolismo , Sementes/química
4.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597276

RESUMO

Chrysanthemum boreale Makino essential oil (CBMEO) has diverse biological activities including a skin regenerating effect. However, its role in muscle atrophy remains unknown. This study explored the effects of CBMEO and its active ingredients on skeletal muscle atrophy using in vitro and in vivo models of muscle atrophy. CBMEO reversed the size decrease of L6 myoblasts under starvation. Among the eight monoterpene compounds of CBMEO without cytotoxicity for L6 cells, sabinene induced predominant recovery of reductions of myotube diameters under starvation. Sabinene diminished the elevated E3 ubiquitin ligase muscle ring-finger protein-1 (MuRF-1) expression and p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylations in starved myotubes. Moreover, sabinene decreased the increased level of reactive oxygen species (ROS) in myotubes under starvation. The ROS inhibitor antagonized expression of MuRF-1 and phosphorylation of MAPKs, which were elevated in starved myotubes. In addition, levels of muscle fiber atrophy and MuRF-1 expression in gastrocnemius from fasted rats were reduced after administration of sabinene. These findings demonstrate that sabinene, a bioactive component from CBMEO, may attenuate skeletal muscle atrophy by regulating the activation mechanism of ROS-mediated MAPK/MuRF-1 pathways in starved myotubes, probably leading to the reverse of reduced muscle fiber size in fasted rats.


Assuntos
/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
5.
Food Funct ; 10(11): 6967-6986, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31599912

RESUMO

Skeletal muscle wasting is highly correlated with not only reduced quality of life but also higher morbidity and mortality. Although an increasing number of patients are suffering from various kinds of muscle atrophy and weakness, there is still no effective therapy available, and skeletal muscle is considered as an under-medicated organ. Food provided not only essential macronutrients but also functional substances involved in the modulation of the physiological systems of our body. Natural constituents from commonly consumed dietary plants, either extracts or compounds, have attracted more and more attention to be developed as agents for preventing and treating muscle wasting due to their safety and effectiveness, as well as structural diversity. This review provides an overview of the mechanistic aspects of muscle wasting, and summarizes the extracts and compounds from food sources as potential therapeutic agents against muscle wasting.


Assuntos
Atrofia Muscular/dietoterapia , Animais , Humanos , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Extratos Vegetais/metabolismo
6.
Nat Commun ; 10(1): 4171, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519904

RESUMO

The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting.


Assuntos
Proteína Semelhante a ELAV 1/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Neoplasias/complicações , Animais , Linhagem Celular , Linhagem Celular Tumoral , Estudos Transversais , Proteína Semelhante a ELAV 1/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout
7.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500089

RESUMO

Previously, we reported that polyphenol-rich fraction (named E80) promotes skeletal muscle hypertrophy induced by functional overload in mice. This study indicates that E80 has potential for affecting skeletal muscle mass. Then, we evaluate the effect of E80 on atrophic and recovery conditions of skeletal muscle in mice. Hindlimb suspension (unloading) and relanding (reloading) are used extensively to observe disuse muscle atrophy and subsequent muscle mass recovery from atrophy. Eight-week old C57BL/6 mice were fed either a normal diet or a diet containing 0.5% E80 for two weeks under conditions of hindlimb suspension and a subsequent 5 or 10 days of reloading. We found that E80 administration did not prevent atrophy during hindlimb suspension, but promoted recovery of slow-twitch (soleus) muscle mass from atrophy induced by hindlimb suspension. After five days of reloading, we discovered that phosphorylation of the Akt/mammalian target of rapamycin (mTOR) pathway proteins, such as Akt and P70 ribosomal protein S6 kinase (S6K), was activated in the muscle. Therefore, E80 administration accelerated mTOR signal and increased protein synthesis in the reloaded soleus muscle.


Assuntos
Camellia sinensis/química , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Elevação dos Membros Posteriores , Masculino , Camundongos Endogâmicos C57BL , Peso Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patologia , Fosforilação , Extratos Vegetais/isolamento & purificação , Polifenóis/isolamento & purificação , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
8.
Biomed Pharmacother ; 117: 109197, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387190

RESUMO

Sucrose nonfermenting AMPK-related kinase (SNARK) is a member of the AMPK family of kinases and has been implicated in the regulation of critical metabolic processes. Recent findings demonstrate that SNARK has an important role in the maintenance of muscle mass with age. Loss of skeletal muscle mass (cachexia) is a key problem for cancer patients. Thus, based on our previous findings with aging, we hypothesized that SNARK would play a role in regulating muscle mass under conditions of cancer cachexia. To test this hypothesis, Lewis Lung Carcinoma tumor cells or vehicle were injected subcutaneously in the right flank of wild type mice, muscle-specific transgenic mice expressing inactive SNARK mutant (SDN) or muscle-specific transgenic mice overexpressing wild-type SNARK (SWT). All tumor-bearing mice presented muscle wasting compared to vehicle-injected mice. However, SDN tumor-bearing mice had more pronounced atrophy compared to wild-type and SWT tumor-bearing mice. Histological analysis confirmed muscle atrophy in tumor-bearing mice, and SDN tumor-bearing mice exhibited a significantly smaller skeletal muscle cross-sectional area than wild-type and SWT tumor-bearing mice. Moreover, SDN tumor-bearing mice had increased skeletal muscle BAX protein expression, a marker of apoptosis, compared to other groups.Thus, lack of SNARK in skeletal muscle aggravates cancer-induced skeletal muscle wasting. These findings uncover a role for SNARK in the maintenance of skeletal muscle mass under cachexia conditions.


Assuntos
Carcinoma Pulmonar de Lewis/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Sacarose/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/fisiologia , Caquexia/metabolismo , Caquexia/patologia , Carcinoma Pulmonar de Lewis/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atrofia Muscular/etiologia
9.
Food Funct ; 10(8): 5152-5165, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373594

RESUMO

The aim of this study was to investigate the effects of dietary ß-hydroxy-ß-methylbutyrate (HMB) on lipopolysaccharide (LPS)-induced muscle atrophy and to investigate the mechanisms involved. Sixty pigs (21 ± 2 days old, 5.86 ± 0.18 kg body weight) were used in a 2 × 3 factorial design and the main factors included diet (0, 0.60%, or 1.20% HMB) and immunological challenge (LPS or saline). After 15 d of treatment with LPS and/or HMB, growth performance, blood parameters, and muscle protein degradation rate were measured. The results showed that in LPS-injected pigs, 0.60% HMB supplementation increased the average daily gain and average daily feed intake and decreased the feed : gain ratio (P < 0.05), with a concurrent increase of lean percentage. Moreover, 0.60% HMB supplementation decreased the serum concentrations of blood urea nitrogen, IL-1ß, and TNF-α and the rate of protein degradation as well as cell apoptosis in selected muscles (P < 0.05). In addition, dietary HMB supplementation (0.60%) regulated the expression of genes involved in mitochondrial biogenesis and increased the phosphorylation of Akt and Forkhead Box O3a (FoxO3a) in selected muscles, accompanied by decreased protein expression of muscle RING finger 1 and muscle atrophy F-box. These results indicate that HMB may exert protective effects against LPS-induced muscle atrophy by normalizing the Akt/FoxO3a axis that regulates ubiquitin proteolysis and by improving mitochondrial biogenesis.


Assuntos
Proteína Forkhead Box O3/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Musculares/metabolismo , Atrofia Muscular/veterinária , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doenças dos Suínos/prevenção & controle , Valeratos/administração & dosagem , Ração Animal/análise , Animais , Feminino , Proteína Forkhead Box O3/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Biogênese de Organelas , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Suínos , Doenças dos Suínos/induzido quimicamente , Doenças dos Suínos/genética , Doenças dos Suínos/metabolismo
10.
Eur J Pharmacol ; 861: 172612, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421088

RESUMO

Denervation caused by sciatic nerve injury has brought great harm to the patients, especially denervation-induced muscle atrophy. The body stress produces a large number of Schwann cells when the sciatic nerve is injured, and the cells secrete some cytokines including ciliary neurotrophic factor (CNTF) that not only play a role in promoting the repair of sciatic nerve, but also maintain the normal physiological function of the muscles surrounding the damaged nerves. CNTF upregulates janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) signals in myoblasts, and consequently accelerates the proliferation and differentiation of myoblasts. This effect on myoblasts is the most effective way to relieve muscle atrophy. Therefore, increasing CNTF is a promising direction to improve muscle atrophy. In the present study, an oleanolic acid derivative, HA-19, increased the proliferation of Schwann cells, and elevated CNTF production of the cells. HA-19 up-regulated the phosphorylation of JAK2 and STAT3 not only by directly acting on myoblasts, but also by increasing the secretion of CNTF of Schwann cells; and consequently, promoted the proliferation and differentiation of myoblasts. In denervation-induced muscle atrophy mice model, treatment with HA-19 significantly increased the weights of tibialis anterior (TA), gastrocnemius (Gastroc.), extensor digitorum longus (EDL), soleus and quadriceps (Quad.) under atrophied state. And, very interestingly, these muscles under normal condition were also strengthened by HA-19. Our finding demonstrated that HA-19 has a great potential as a lead compound for the drug discovery of anti-denervation-induced muscle atrophy.


Assuntos
Fator Neurotrófico Ciliar/metabolismo , Janus Quinase 2/metabolismo , Atrofia Muscular/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Denervação/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/patologia , Ácido Oleanólico/uso terapêutico , Fosforilação/efeitos dos fármacos , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia , Regulação para Cima/efeitos dos fármacos
11.
Redox Biol ; 26: 101308, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31470261

RESUMO

Mitochondrial dysfunction, reactive oxygen species (ROS) and oxidative damage have been implicated to play a causative role in age-related skeletal muscle atrophy and weakness (i.e. sarcopenia). Mice lacking the superoxide scavenger CuZnSOD (Sod1-/-) exhibit high levels of oxygen-derived radicals and oxidative damage, associated with neuronal and muscular phenotypes consistent with sarcopenia. We used magnetic resonance imaging (MRI) technology combined with immunospin-trapping (IST) to measure in vivo free radical levels in skeletal muscle from wildtype, Sod1-/- and SynTgSod1-/- mice, a mouse model generated using targeted expression of the human Sod1 transgene specifically in neuronal tissues to determine the impact of motor neuron degeneration in muscle atrophy. By combining the spin trap DMPO (5,5-dimethyl-1-pyrroline N-oxide) and molecular MRI (mMRI), we monitored the level of free radicals in mouse hindlimb muscle. The level of membrane-bound macromolecular radicals in the quadriceps muscle was elevated by ~3-fold in Sod1-/- mice, but normalized to wildtype levels in SynTgSod1-/- rescue mice. Skeletal muscle mass was reduced by ~25-30% in Sod1-/- mice, but fully reversed in muscle from SynTgSod1-/- mice. Using perfusion MRI we also measured the dynamics of blood flow within mouse hindlimb. Relative muscle blood flow in Sod1-/- is decreased to ~50% of wildtype and remained low in the SynTgSod1-/- mice. Our findings are significant in that we have shown for the first time that in vivo free radical production in skeletal muscle is directly correlated to muscle atrophy in an experimental model of oxidative stress. Neuron-specific expression of CuZnSOD reverses the in vivo free radical production in skeletal muscle in the Sod1-/- mouse model and prevents muscle atrophy. These results further support the feasibility of using in vivo assessments of redox status in the progression of a pathological process such as sarcopenia. This approach can also be valuable for evaluating responses to pharmacologic interventions.


Assuntos
Radicais Livres/metabolismo , Imagem por Ressonância Magnética , Imagem Molecular , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/metabolismo , Estresse Oxidativo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
12.
J Physiol Sci ; 69(5): 757-767, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273678

RESUMO

The effects of a combination of the antioxidant astaxanthin (AX) and electrical stimulation (ES) on muscle mass and mitochondrial oxidative capacity were investigated in the soleus muscle of hindlimb unloaded rats. Five groups of male Sprague-Dawley rats were used; control, 1-week hindlimb unloading (HU), HU + AX, HU + ES, and HU + AX + ES. Respective rats in the AX groups received 50-mg/kg AX twice daily during HU. Calf muscles of rats in the ES groups were electrically stimulated for 240 s/day during HU. One-week HU decreased muscle mass along with decreased FoxO3a phosphorylation and increased ubiquitinated proteins expressions, decreased oxidative enzymatic activity accompanied with decline in PGC-1α protein expression, and increased reactive oxygen species production. However, the combination treatment could synergistically attenuate/suppress all HU-related changes, suggesting protective effects on muscle atrophy and decreased muscle oxidative capacity due to chronic neuromuscular inactivity.


Assuntos
Membro Posterior/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Oxirredução/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Suplementos Nutricionais , Estimulação Elétrica/métodos , Membro Posterior/metabolismo , Elevação dos Membros Posteriores/métodos , Masculino , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/farmacologia
13.
Arch Physiol Biochem ; 125(5): 470-477, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31291133

RESUMO

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


Assuntos
Diabetes Mellitus Experimental/complicações , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/complicações , Atrofia Muscular/prevenção & controle , Niacinamida/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Nutrients ; 11(8)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344809

RESUMO

Military personnel may be exposed to circumstances (e.g., large energy deficits, sleep deprivation, cognitive demands, and environmental extremes) of external stressors during training and combat operations (i.e., operational stressors) that combine to degrade muscle protein. The loss of muscle protein is further exacerbated by frequent periods of severe energy deficit. Exposure to these factors results in a hypogonadal state that may contribute to observed decrements in muscle mass. In this review, lessons learned from studying severe clinical stressed states and the interventions designed to mitigate the loss of muscle protein are discussed in the context of military operational stress. For example, restoration of the anabolic hormonal status (e.g., testosterone, insulin, and growth hormone) in stressed physiological states may be necessary to restore the anabolic influence derived from dietary protein on muscle. Based on our clinical experiences, restoration of the normal testosterone status during sustained periods of operational stress may be advantageous. We demonstrated that in severe burn patients, pharmacologic normalization of the anabolic hormonal status restores the anabolic stimulatory effect of nutrition on muscle by improving the protein synthetic efficiency and limiting amino acid loss from skeletal muscle. Furthermore, an optimal protein intake, and in particular essential amino acid delivery, may be an integral ingredient in a restored anabolic response during the stress state. Interventions which improve the muscle net protein balance may positively impact soldier performance in trying conditions.


Assuntos
Proteínas na Dieta/administração & dosagem , Medicina Militar , Militares , Contração Muscular , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/prevenção & controle , Doenças Profissionais/prevenção & controle , Estresse Fisiológico , Animais , Proteínas na Dieta/metabolismo , Metabolismo Energético , Hormônios/metabolismo , Humanos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Estado Nutricional , Doenças Profissionais/metabolismo , Doenças Profissionais/patologia , Doenças Profissionais/fisiopatologia , Saúde do Trabalhador , Fatores de Proteção , Fatores de Risco
15.
Life Sci ; 233: 116699, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356902

RESUMO

AIMS: Skeletal muscle wasting is associated with many chronic diseases. Effective prevention and treatment of muscle wasting remain as a challenging task due to incomplete understanding of mechanisms by which muscle mass is maintained and regulated. This study investigated the functional role of Ubiquitin C-terminal hydrolase L1 (UCHL1) in skeletal muscle. MAIN METHODS: Mice with skeletal muscle specific gene knockout of UCHL1 and C2C12 myoblast cells with UCHL1 knockdown were used. Muscle fiber types and size were measured using tissue or cell staining. The mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 activities were assessed with the phosphorylation of their downstream targets. KEY FINDINGS: In mouse skeletal muscle, UCHL1 was primarily expressed in slow twitch muscle fibers. Mice with skeletal muscle specific knockout (skmKO) of UCHL1 exhibited enlarged muscle fiber sizes in slow twitch soleus but not fast twitch extensor digitorum longus (EDL) muscle. Meanwhile, UCHL1 skmKO enhanced mTORC1 activity and reduced mTORC2 activity in soleus but not in EDL. Consistently, in C2C12 cells, UCHL1 knockdown increased the myotube size, enhanced mTORC1 activity, and reduced mTORC2 activities as compared with control cells. UCHL1 knockdown did not change the major proteins of mTOR complex but decreased the protein turnover of PRAS40, an inhibitory factor of mTORC1. SIGNIFICANCE: These data revealed a novel function of UCHL1 in regulation of mTORC1 activity and skeletal muscle growth in slow twitch skeletal muscle. Given the upregulation of UCHL1 in denervation and spinal muscle atrophy, our finding advances understanding of regulators that are involved in muscle wasting.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fibras Musculares de Contração Lenta/fisiologia , Músculo Esquelético/fisiologia , Atrofia Muscular/fisiopatologia , Mioblastos/fisiologia , Ubiquitina Tiolesterase/fisiologia , Animais , Células Cultivadas , Feminino , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Knockout , Fibras Musculares de Contração Lenta/citologia , Músculo Esquelético/citologia , Atrofia Muscular/metabolismo , Mioblastos/citologia , Fosforilação , Ubiquitina Tiolesterase/antagonistas & inibidores
16.
Mar Drugs ; 17(6)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242648

RESUMO

Obesity is known to cause skeletal muscle wasting. This study investigated the effect and the possible mechanism of fish oil on skeletal muscle wasting in an obese rat model. High-fat (HF) diets were applied to induce the defects of lipid metabolism in male Sprague-Dawley rats with or without substitution of omega-3 fatty acids-enriched fish oil (FO, 5%) for eight weeks. Diets supplemented with 5% FO showed a significant decrease in the final body weight compared to HF diet-fed rats. The decreased soleus muscle weights in HF diet-fed rats could be improved by FO substitution. The decreased myosin heavy chain (a muscle thick filament protein) and increased FOXO3A and Atrogin-1 (muscle atrophy-related proteins) protein expressions in soleus muscles of HF diet-fed rats could also be reversed by FO substitution. FO substitution could also significantly activate adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation, peroxisome-proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α), and PPARγ protein expression and lipoprotein lipase (LPL) mRNA expression in soleus muscles of HF diet-fed rats. These results suggest that substitution of FO exerts a beneficial improvement in the imbalance of lipid and muscle metabolisms in obesity. AMPK/PGC-1α signaling may play an important role in FO-prevented obesity-induced muscle wasting.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Óleos de Peixe/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Oncol Rep ; 42(2): 479-494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233199

RESUMO

Skeletal muscle wasting is a feature of cancer cachexia that increases patient morbidity and mortality. Matrine, the main bioactive component of Sophora flavescens, has been approved for the prevention and therapy of cancer cachexia in China. However, to the best of our knowledge, its mechanism in improving muscle wasting remains unknown. The present study demonstrated that matrine increases muscle fiber size and muscle mass in an in vivo CT26 colon adenocarcinoma cachexia mouse model. Concurrently, other cachexia symptoms, including body and organ weight loss, were alleviated. In in vitro experiments, matrine substantially improved C2C12 myoblast differentiation with or without dexamethasone treatment. In addition, matrine reduced C2C12 myotube atrophy and apoptosis induced by dexamethasone, tumor necrosis factor α and conditioned medium. Two E3 ubiquitin ligases, muscle RING­finger containing protein­1 and muscle atrophy F-box protein, which are specifically expressed in wasting skeletal muscle, were also significantly downregulated (P<0.05) by matrine both in C2C12 myotubes and skeletal muscle. Furthermore, matrine increased the phosphorylation of Akt, mTOR and FoxO3α in the atrophying C2C12 myotube induced by dexamethasone. In conclusion, matrine can alleviate muscle atrophy and improve myoblast differentiation possibly by inhibiting E3 ubiquitin ligases and activating the Akt/mTOR/FoxO3α signaling pathway.


Assuntos
Alcaloides/farmacologia , Caquexia/tratamento farmacológico , Neoplasias do Colo/complicações , Regulação da Expressão Gênica/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Quinolizinas/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Apoptose , Caquexia/etiologia , Caquexia/metabolismo , Proliferação de Células , Neoplasias do Colo/induzido quimicamente , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Humanos , Masculino , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/toxicidade
18.
Mar Drugs ; 17(5)2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31083497

RESUMO

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 µM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy.


Assuntos
Dexametasona/toxicidade , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Peptídeos/farmacologia , Proteínas de Plantas/farmacologia , Rodófitas/química , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Lisossomos/metabolismo , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Peptídeos/química , Proteínas de Plantas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
19.
Endocrinology ; 160(6): 1536-1546, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127274

RESUMO

Allan-Herndon-Dudley syndrome (AHDS) is a severe genetic disease caused by mutations in the monocarboxylate transporter 8 (MCT8) gene. MCT8 mediates transport of thyroid hormones in and out of cells, which is thought to play a pivotal role for embryonic and postnatal development of the human brain. Disconcertingly, MCT8R271H leads to a severe form of AHDS but shows residual transport activity when expressed in several types of cultured cells. Here we try to determine the mechanism behind the transport function of MCT8R271H found in overexpressing cell systems. Mutations of Arg271 were introduced into human MCT8 and stably transfected into Madin-Darby canine kidney cells and the human-derived cell line JEG1. Radioactive thyroid hormone-uptake experiments were performed to analyze the pH-dependent effect of the mutation on transport activity. Arg271His transports thyroid hormones in and out of cells in a pH-dependent manner. Its transport activity increases below pH 7.3 and is clearly diminished at physiological pH. The Michaelis constant of the mutant is unaltered, whereas the maximum velocity is reduced. The expression of Arg271His in JEG1 cells leads to an almost nonfunctional transporter at physiological pH replicating the human phenotype for this mutant in vitro and demonstrates, again, that mutant MCT8 activity depends on cellular background. The protonation of His271 at acidic pH restores activity of the mutant protein, which is not active in its deprotonated form at physiological pH. Thus, experimental parameters must be controlled carefully when modeling MCT8 deficiency in cells.


Assuntos
Transportadores de Ácidos Monocarboxílicos/genética , Mutação , Fenótipo , Hormônios Tireóideos/metabolismo , Animais , Linhagem Celular , Cães , Humanos , Células Madin Darby de Rim Canino , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Transporte Proteico
20.
Biomed Res Int ; 2019: 7387131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061826

RESUMO

Background: Significant proportion of rotator cuff tears (RCTs) in clinical field are of a kind of repairable tear wherein the degree of fatty infiltration is of Goutallier stage 1 or stage 2. Therefore, the animal model, showing similar fatty infiltration, seems preferable for researches. The purpose of this study is to find out the proper time frame in which there is Goutallier stage 1 or stage 2 fatty infiltration in the rabbit RCT model for the research of repairable RCT in humans. Methods: Supraspinatus tendon tears were created in forty male New Zealand white rabbits at their right shoulder (n= 8 for each group), and a sham operation on the left shoulder. Rabbits were divided into five groups (2nd, 4th, 6th, 8th, and 12th weeks). Specimens were harvested from the central portion of the supraspinatus muscle for haematoxylin and eosin (H &E) staining, followed by histological and Goutallier grading evaluation. Results are expressed as mean ± standard deviation by Sigma Plot software (version 7.0). Results: At two weeks, mainly lipoblasts were observed around the muscle fibers, and at four weeks these lipoblasts were replaced by mature adipocytes with fatty infiltration amount (2.13 ± 0.35). The degree of muscle atrophy was (1.50 ± 0.53) at four weeks compared to sham group (0.88 ± 0.64) with significant difference (p < 0.05). The inflammatory process appeared as two phases. At two weeks, it was increased with grading value (1.88 ± 0.35). However, in the four-week group, it showed a sharp decrease (0.50 ± 0.53). At six weeks, inflammation reappeared to increase (1.13 ± 0.83). Then, a gradual decline appeared at eight weeks (0.88 ± 0.83) and at 12 weeks (0.50 ± 0.92). Conclusions: At two and four weeks, both fat distribution in rabbit supraspinatus muscles and Goutallier grading scale mostly appeared as grade 2. Therefore, we can consider four weeks to be a suitable period for making a repairable RCT animal model for the human research, considering the early acute tissue reaction at 2 weeks after the tendon tears.


Assuntos
Tecido Adiposo/metabolismo , Atrofia Muscular/metabolismo , Lesões do Manguito Rotador/metabolismo , Manguito Rotador/metabolismo , Tecido Adiposo/patologia , Animais , Modelos Animais de Doenças , Humanos , Masculino , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Coelhos , Manguito Rotador/patologia , Lesões do Manguito Rotador/patologia , Ombro/patologia , Fatores de Tempo
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