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1.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33649814

RESUMO

Muscle atrophy, a side effect from administration of the anti­inflammatory medication dexamethasone (DEX), is preventable by concomitant administration of the major monomeric constituent of Panax ginseng C.A. Meyer, 20(S)­ginsenoside Rg3 (S­Rg3). Putative S­Rg3­associated prevention of DEX­induced muscle atrophy may involve S­Rg3 mitigation of DEX­induced mitochondrial dysfunction. In the present study, MTT assays revealed enhanced cell viability following S­Rg3 treatment of DEX­injured C2C12 myotubes. Subsequent PCR and western blotting results demonstrated S­Rg3­induced reduction of expression of muscle atrophy F­box protein (atrogin­1) and muscle RING­finger protein­1, proteins previously linked to muscle atrophy. Additionally, S­Rg3 treatment of DEX­injured myotubes led to aggregation of Rg3 monomers in cells and dose­dependent increases in cellular mitochondrial basal respiratory oxygen consumption rate and intracellular ATP levels compared with their levels in untreated DEX­injured myotubes. In addition, S­Rg3 treatment significantly reversed DEX­induced reductions of expression of key mitochondrial respiratory electron transport chain subunits of protein complexes II, III and V in DEX­injured myotube cells. Furthermore, S­Rg3 alleviation of mitochondrial dysfunction associated with DEX­induced injury of C2C12 myotubes was linked to S­Rg3­associated decreases in both forkhead box O3 (FoxO3) protein expression and phosphorylation of AMP­activated protein kinase (AMPK). Collectively, these results implicate S­Rg3 modulation of signaling within the AMPK­FoxO3 pathway as a putative mechanism underlying S­Rg3 alleviation of DEX­induced muscle atrophy.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Dexametasona/farmacologia , Proteína Forkhead Box O3/genética , Ginsenosídeos/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Camundongos , Mitocôndrias Musculares/metabolismo , Modelos Biológicos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Transdução de Sinais/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
2.
Nutrients ; 13(2)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546195

RESUMO

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is expressed in skeletal muscles and regulates systemic metabolism. Thus, nutraceuticals targeting skeletal muscle PGC-1α have attracted attention to modulate systemic metabolism. As auraptene contained in citrus fruits promotes lipid metabolism and improves mitochondrial respiration, it could increase mitochondrial function through PGC-1α. Therefore, we hypothesized that PGC-1α is activated by auraptene and investigated its effect using Citrus hassaku extract powder (CHEP) containing >80% of auraptene. C2C12 myotubes were incubated with vehicle or CHEP for 24 h; C57BL/6J mice were fed a control diet or a 0.25% (w/w) CHEP-containing diet for 5 weeks. PGC-1α protein level and mitochondrial content increased following CHEP treatment in cultured myotubes and skeletal muscles. In addition, the number of oxidative fibers increased in CHEP-fed mice. These findings suggest that CHEP-mediated PGC-1α upregulation induced mitochondrial biogenesis and fiber transformation to oxidative fibers. Furthermore, as CHEP increased the expression of the protein sirtuin 3 and of phosphorylated AMP-activated protein kinase (AMPK) and the transcriptional activity of PGC-1α, these molecules might be involved in CHEP-induced effects in skeletal muscles. Collectively, our findings indicate that CHEP mediates PGC-1α expression in skeletal muscles and may serve as a dietary supplement to prevent metabolic disorders.


Assuntos
Citrus/química , Mitocôndrias Musculares/efeitos dos fármacos , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/fisiologia , Fibras Musculares de Contração Rápida/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Mioblastos , Oxirredução , Pós , Regulação para Cima/efeitos dos fármacos
3.
Am J Physiol Cell Physiol ; 320(4): C577-C590, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33439777

RESUMO

The peroxisome proliferator-activated receptors (PPARs) have been previously implicated in the pathophysiology of skeletal muscle dysfunction in women with breast cancer (BC) and animal models of BC. This study investigated alterations induced in skeletal muscle by BC-derived factors in an in vitro conditioned media (CM) system and tested the hypothesis that BC cells secrete a factor that represses PPAR-γ (PPARG) expression and its transcriptional activity, leading to downregulation of PPARG target genes involved in mitochondrial function and other metabolic pathways. We found that BC-derived factors repress PPAR-mediated transcriptional activity without altering protein expression of PPARG. Furthermore, we show that BC-derived factors induce significant alterations in skeletal muscle mitochondrial function and lipid accumulation, which are rescued with exogenous expression of PPARG. The PPARG agonist drug rosiglitazone was able to rescue BC-induced lipid accumulation but did not rescue effects of BC-derived factors on PPAR-mediated transcription or mitochondrial function. These data suggest that BC-derived factors alter lipid accumulation and mitochondrial function via different mechanisms that are both related to PPARG signaling, with mitochondrial dysfunction likely being altered via repression of PPAR-mediated transcription, and lipid accumulation being altered via transcription-independent functions of PPARG.


Assuntos
Neoplasias da Mama/metabolismo , Caquexia/metabolismo , Metabolismo dos Lipídeos , Mitocôndrias Musculares/metabolismo , Mioblastos Esqueléticos/metabolismo , PPAR gama/metabolismo , Comunicação Parácrina , Animais , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Caquexia/etiologia , Caquexia/genética , Caquexia/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/metabolismo , Feminino , Células HEK293 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/patologia , PPAR gama/agonistas , PPAR gama/genética , Rosiglitazona/farmacologia , Transdução de Sinais , Transcrição Genética
4.
Nat Metab ; 3(1): 107-117, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33462512

RESUMO

Creatine availability in adipose tissue has been shown to have profound effects on thermogenesis and energy balance in mice. However, whether dietary creatine supplementation affects brown adipose tissue (BAT) activation in humans is unclear. In the present study, we report the results of a double-blind, randomized, placebo-controlled, cross-over trial (NCT04086381) in which 14 young, healthy, vegetarian adults, who are characterized by low creatine levels, received 20 g of creatine monohydrate per day or placebo. Participants were eligible if they met the following criteria: male or female, white, aged 18-30 years, consuming a vegetarian diet (≥6 months) and body mass index 20-25 kg m-2. BAT activation after acute cold exposure was determined by calculating standard uptake values (SUVs) acquired by [18F]fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. BAT volume (-31.32 (19.32) SUV (95% confidence interval (CI) -73.06, 10.42; P = 0.129)), SUVmean (-0.34 (0.29) SUV (95% CI -0.97, 0.28; P = 0.254)) and SUVmax (-2.49 (2.64) SUV (95% CI -8.20, 3.21; P = 0.362)) following acute cold exposure were similar between placebo and creatine supplementation. No side effects of creatine supplementation were reported; one participant experienced bowel complaints during placebo, which resolved without intervention. Our data show that creatine monohydrate supplementation in young, healthy, lean, vegetarian adults does not enhance BAT activation after acute cold exposure.


Assuntos
Tecido Adiposo Marrom/metabolismo , Creatina/farmacologia , Vegetarianos , Tecido Adiposo Marrom/efeitos dos fármacos , Adolescente , Adulto , Composição Corporal , Índice de Massa Corporal , Temperatura Baixa , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adulto Jovem
5.
Metabolism ; 114: 154416, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33137378

RESUMO

CONTEXT: In this study, we aimed to identify the determinants of mitochondrial dysfunction in skeletal muscle (SKLM) of subjects with type 2 diabetes (T2DM), and to evaluate the effect of pioglitazone (PIO) on SKLM mitochondrial proteome. METHODS: Two different groups of adults were studied. Group I consisted of 8 individuals with normal glucose tolerance (NGT) and 8 with T2DM, subjected to SKLM mitochondrial proteome analysis by 2D-gel electrophoresis followed by mass spectrometry-based protein identification. Group II included 24 individuals with NGT and 24 with T2DM, whose SKLM biopsies were subjected to immunoblot analysis. Of the 24 subjects with T2DM, 20 were randomized to receive placebo or PIO (15 mg daily) for 6 months. After 6 months of treatment, SKLM biopsy was repeated. RESULTS: Mitochondrial proteomic analysis on Group I revealed that several mitochondrial proteins involved in oxidative metabolism were differentially expressed between T2DM and NGT groups, with a downregulation of ATP synthase alpha chain (ATP5A), electron transfer flavoprotein alpha-subunit (ETFA), cytochrome c oxidase subunit VIb isoform 1 (CX6B1), pyruvate dehydrogenase protein X component (ODPX), dihydrolipoamide dehydrogenase (DLDH), dihydrolipoamide-S-succinyltransferase (DLST), and mitofilin, and an up-regulation of hydroxyacyl-CoA-dehydrogenase (HCDH), 3,2-trans-enoyl-CoA-isomerase (D3D2) and delta3,5-delta2,4-dienoyl-CoA-isomerase (ECH1) in T2DM as compared to NGT subjects. By immunoblot analysis on SKLM lysates obtained from Group II we confirmed that, in comparison to NGT subjects, those with T2DM exhibited lower protein levels of ATP5A (-30%, P = 0.006), ETFA (-50%, P = 0.02), CX6B1 (-30%, P = 0.03), key factors for ATP biosynthesis, and of the structural protein mitofilin (-30%, P = 0.01). T2DM was associated with a reduced abundance of the enzymes involved in the Krebs cycle DLST and ODPX (-20%, P ≤ 0.05) and increased levels of HCDH and ECH1, enzymes implicated in the fatty acid catabolism (+30%, P ≤ 0.05). In subjects with type 2 diabetes treated with PIO for 6 months we found a restored SKLM protein abundance of ATP5A, ETFA, CX6B1, and mitofilin. Moreover, protein levels of HCDH and ECH1 were reduced by -10% and - 15% respectively (P ≤ 0.05 for both) after PIO treatment. CONCLUSION: Type 2 diabetes is associated with reduced levels of mitochondrial proteins involved in oxidative phosphorylation and an increased abundance of enzymes implicated in fatty acid catabolism in SKLM. PIO treatment is able to improve SKLM mitochondrial proteomic profile in subjects with T2DM.


Assuntos
Trifosfato de Adenosina/biossíntese , Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/efeitos dos fármacos , Pioglitazona/farmacologia , Adulto , Feminino , Glucose/metabolismo , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Fosforilação Oxidativa , Proteômica
6.
Am J Physiol Regul Integr Comp Physiol ; 320(3): R362-R376, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356878

RESUMO

Migratory birds may benefit from diets rich in polyunsaturated fatty acids (PUFAs) that could improve exercise performance. Previous investigations suggest that different types of birds may respond differently to PUFA. We established muscle myocyte cell culture models from muscle satellite cells of a migratory passerine songbird (yellow-rumped warbler, Setophaga coronata coronata) and a nonpasserine shorebird (sanderling, Calidris alba). We differentiated and treated avian myotubes and immortalized murine C2C12 myotubes with n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and with monounsaturated oleic acid (OA) to compare effects on aerobic performance, metabolic enzyme activities, key fatty acid (FA) transporters, and expression of peroxisome proliferator-activated receptors (PPARs). Sanderling and C2C12 myotubes increased expression of PPARs with n-3 PUFA treatments, whereas expression was unchanged in yellow-rumped warblers. Both sanderlings and yellow-rumped warblers increased expression of fatty acid transporters, whereas C2C12 cells decreased expression following n-3 PUFA treatments. Only yellow-rumped warbler myotubes increased expression of some metabolic enzymes, whereas the sanderling and C2C12 cells were unchanged. PUFA supplementation in C2C12 myotubes increased mitochondrial respiratory chain efficiency, whereas sanderlings increased proton leak-associated respiration and maximal respiration (measurements were not made in warblers). This research indicates that songbirds and shorebirds respond differently to n-3 PUFA and provides support for the hypothesis that n-3 PUFA increase the aerobic capacity of migrant shorebird muscle, which may improve overall endurance flight performance.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Metabolismo Energético/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Ácido Oleico/farmacologia , Aves Canoras/metabolismo , Animais , Comportamento Animal , Linhagem Celular , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Voo Animal , Masculino , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Especificidade da Espécie
7.
Toxicol Appl Pharmacol ; 411: 115366, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33316273

RESUMO

Mitochondrial dysfunction is a well-characterized consequence of spinal cord injury (SCI). We previously reported that treatment with the FDA-approved ß2-adrenergic receptor agonist formoterol beginning 8 h post-SCI induces mitochondrial biogenesis (MB) and improves body composition and locomotor recovery in female mice. To determine the time-to-treatment window of formoterol, female mice were subjected to 80 kdyn contusion SCI and daily administration of vehicle or formoterol (0.3 mg/kg) beginning 24 h after injury. This delayed treatment paradigm improved body composition in female mice by 21 DPI, returning body weight to pre-surgery weight and restoring gastrocnemius mass to sham levels; however, there was no effect on locomotor recovery, as measured by the Basso-Mouse Scale (BMS), or lesion volume. To assess the cross-sex potential of formoterol, injured male mice were treated with vehicle or formoterol (0.3 or 1.0 mg/kg) beginning 8 h after SCI. Formoterol also improved body composition post-SCI in male mice, restoring body weight and muscle mass regardless of dose. Interestingly, however, improved BMS scores and decreased lesion volume was observed only in male mice treated with 0.3 mg/kg. Additionally, 0.3 mg/kg formoterol induced MB in the gastrocnemius and injured spinal cord, as evidenced by increased MB protein expression and mitochondrial number. These data indicate that formoterol treatment improves recovery post-SCI in both male and female mice in a dose- and initiation time-dependent manner. Furthermore, formoterol-induced functional recovery post-SCI is not directly associated with peripheral effects, such as muscle mass and body weight.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Biogênese de Organelas , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Tempo para o Tratamento , Animais , Composição Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Receptores Adrenérgicos beta 2/metabolismo , Recuperação de Função Fisiológica , Fatores Sexuais , Medula Espinal/metabolismo , Medula Espinal/ultraestrutura , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Fatores de Tempo
8.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375170

RESUMO

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.


Assuntos
Aminoquinolinas/farmacologia , Benzamidas/farmacologia , Debilidade Muscular/prevenção & controle , Atrofia Muscular/prevenção & controle , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Fatores Etários , Aminoquinolinas/administração & dosagem , Animais , Benzamidas/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Injeções Intraperitoneais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Debilidade Muscular/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio/metabolismo , Proteína Desacopladora 1/metabolismo
9.
Ecotoxicol Environ Saf ; 205: 111127, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846293

RESUMO

Trichlorfon is an organophosphate insecticide that is widely used on fish farms to control parasitic infections. It has been detected in freshwater ecosystems as well as in fishery products. There is a growing body of evidence to suggest that certain feed additives may reduce or prevent pesticide-induced toxicity in fish. The aim of the present study was to determine whether acute exposure to trichlorfon would alter bioenergetic homeostasis and alter fatty acid profiles in muscles of silver catfish (Rhamdia quelen). We also sought to determine whether rutin prevents or reduces these effects. Cytosolic and mitochondrial creatine kinase (CK) and activities of complexes II-III and IV in muscle were significantly inhibited by exposure to 11 mg/L trichlorfon for 48 h compared to effects in the unexposed group. Total content of polyunsaturated fatty acids (omega-3 and omega-6) were significantly lower in muscle of silver catfish exposed to 11 mg/L trichlorfon for 48 h than in the unexposed group. Addition of 3 mg rutin/kg feed increased CK activity and prevented inhibition of complex IV activity, as well as preventing all alterations of muscle fatty acid profiles elicited by exposure to trichlorfon. No significant differences were observed between groups with respect to muscle adenylate kinase or pyruvate kinase activities, as well as total content of saturated and monounsaturated fatty acids. Our findings suggest that exposure (48 h) to 11 mg trichlorfon/L water inhibits cytosolic and mitochondrial CK activity in muscle. Trichlorfon also affects activities of complexes II-III and IV in respiratory chain, with important consequences for adenosine triphosphate production. The pesticide alters fatty acid profiles in the fish and endangers human consumers of the product. The most important finding of the present study is that inclusion of rutin improves bioenergetic homeostasis and muscle fatty acid profiles, suggesting that it reduces trichlorfon-induced muscle damage.


Assuntos
Peixes-Gato/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Inseticidas/toxicidade , Músculos/efeitos dos fármacos , Rutina/farmacologia , Triclorfon/toxicidade , Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Ração Animal , Animais , Peixes-Gato/crescimento & desenvolvimento , Creatina Quinase/metabolismo , Dieta , Aditivos Alimentares , Homeostase , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculos/metabolismo
10.
Cardiovasc Drugs Ther ; 34(5): 605-618, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32564303

RESUMO

OBJECTIVE: We have shown previously that diallyl trisulfide (DATS) ameliorates mitochondrial fission and oxidative stress in a hyperglycemia-induced endothelial apoptosis and diabetic mouse model. The aim of this study was to investigate whether DATS mitigates Ang II-induced vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling, and if so, to determine the underlying molecular events. METHODS: Male C57BL/6 mice were used to establish a vascular remodeling model by continuous 2-week Ang II infusion using a subcutaneous osmotic pump. Animals were intraperitoneally injected with DATS or vehicle. Physiological parameters, vascular morphology, and molecular markers were assessed. For in vitro studies, VSMCs were pretreated with or without DATS for 1 h, then were stimulated with Ang II, and mitochondrial morphology and phenotypic switching of VSMCs were also measured. RESULTS: In primary mouse VSMCs, we found that Drp1-dependent mitochondrial fission regulated mitochondrial reactive oxygen species (mtROS) generation, which eventually promoted Ang II-induced VSMC proliferation, migration, and phenotypic switching. Moreover, Ang II was found to up-regulate the Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which regulated mitochondrial fission and VSMC phenotypic switching by phosphorylating Drp1. However, the biological effect of Ang II was abrogated by DATS. Consistent with the effects in VSMCs, we found that DATS markedly alleviated mitochondrial fission, VSMC differentiation, and vessel wall thickening in an animal model of Ang II-induced vascular remodeling, which was regulated by the ROCK1/Drp1 signal. CONCLUSIONS: Our findings showed that DATS mitigated Ang II-induced vascular remodeling by suppressing Drp1-mediated mitochondrial fission in an ROCK1-dependent manner.


Assuntos
Compostos Alílicos/farmacologia , Hipertensão/tratamento farmacológico , Mitocôndrias Musculares/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Sulfetos/farmacologia , Remodelação Vascular/efeitos dos fármacos , Angiotensina II , Animais , Movimento Celular/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Dinaminas/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Fenótipo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo
11.
Am J Physiol Endocrinol Metab ; 319(2): E345-E353, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32543943

RESUMO

Type 1 and type 2 diabetes are both tightly associated with impaired glucose control. Although both pathologies stem from different mechanisms, a reduction in insulin action coincides with drastic metabolic dysfunction in skeletal muscle and metabolic inflexibility. However, the underlying explanation for this response remains poorly understood, particularly since it is difficult to distinguish the role of attenuated insulin action from the detrimental effects of reactive lipid accumulation, which impairs mitochondrial function and promotes reactive oxygen species (ROS) emission. We therefore utilized streptozotocin to examine the effects of acute insulin deprivation, in the absence of a high-lipid/nutrient excess environment, on the regulation of mitochondrial substrate sensitivity and ROS emission. The ablation of insulin resulted in reductions in absolute mitochondrial oxidative capacity and ADP-supported respiration and reduced the ability for malonyl-CoA to inhibit carnitine palmitoyltransferase I (CPT-I) and suppress fatty acid-supported respiration. These bioenergetic responses coincided with increased mitochondrial-derived H2O2 emission and lipid transporter content, independent of major mitochondrial substrate transporter proteins and enzymes involved in fatty acid oxidation. Together, these data suggest that attenuated/ablated insulin signaling does not affect mitochondrial ADP sensitivity, whereas the increased reliance on fatty acid oxidation in situations where insulin action is reduced may occur as a result of altered regulation of mitochondrial fatty acid transport through CPT-I.


Assuntos
Ácidos Graxos/fisiologia , Insulina/deficiência , Mitocôndrias Musculares/metabolismo , Difosfato de Adenosina/farmacologia , Animais , Transporte Biológico/fisiologia , Carnitina O-Palmitoiltransferase/metabolismo , Peróxido de Hidrogênio/metabolismo , Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/ultraestrutura , Oxirredução , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina/farmacologia
12.
Biochem Biophys Res Commun ; 526(4): 1069-1076, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32305136

RESUMO

Obesity-induced fat ectopic deposition results in mitochondrial dysfunction and oxidative stress in skeletal muscle, which could impair the quality and function of the skeletal muscle. Human fibroblast growth factor 19 (FGF19) acts as a vital metabolic regulator of bile acid synthesis and metabolic homeostasis. Recent studies have shown that FGF19 regulates skeletal muscle mass through the enlargement of muscle fiber size and protects muscles from atrophy. However, the role of FGF19 in regulating mitochondrial function and the antioxidant response in skeletal muscle remains unknown. Therefore, we investigated the effect of FGF19 on palmitic acid (PA)-induced mitochondrial dysfunction and oxidative stress in C2C12 cells. In this study, we found that FGF19 can increase the mRNA and protein expression levels of mitochondrial biogenesis regulators (PGC-1α, Nrf-1, and TFAM) and antioxidant response regulators (Nrf-2 and HO-1), alleviating PA-induced mitochondrial dysfunction and oxidative stress. However, the regulatory effect of FGF19 was blocked by Compound C, an AMP-activated protein kinase (AMPK) inhibitor, and siRNA knockdown of PGC-1a. Taken together, these findings indicate that FGF19 might promote mitochondrial biogenesis and antioxidant response via the AMPK/PGC-1α pathway, attenuating the effect of PA on mitochondrial dysfunction and oxidative stress; therefore, FGF19 might be a potential therapeutic target for the effects of obesity on skeletal muscle.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/toxicidade , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Animais , Antioxidantes/metabolismo , Linhagem Celular , Humanos , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Biogênese de Organelas , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
13.
Rev Mal Respir ; 37(3): 201-204, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32139106

RESUMO

The main purpose of this review is to highlight mitochondria as a new therapeutic target to prevent bronchial smooth muscle (BSM) remodeling in asthma. Severe asthmatic patients, representing 5-10% of all asthmatics, are characterized by an increased BSM mass which is highly correlated with the severity of the disease and the rate of exacerbations. None of the current asthma therapies are effective in reducing BSM remodelling. This review, based on the current literature, reports the role of mitochondria in BSM, particularly in calcium signaling.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Brônquios , Mitocôndrias Musculares/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Animais , Antiasmáticos/administração & dosagem , Asma/metabolismo , Asma/patologia , Brônquios/citologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/ultraestrutura , Sistemas de Liberação de Medicamentos/métodos , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias Musculares/metabolismo , Terapia de Alvo Molecular/tendências , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/ultraestrutura , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Terapias em Estudo/métodos , Terapias em Estudo/tendências
14.
Sci Rep ; 10(1): 1125, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980663

RESUMO

Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD) is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca2+) buffering within, and the regenerative capacity of, dystrophic muscle. Therefore, increasing the metabogenic potential could represent an effective treatment avenue. The aim of our study was to determine the efficacy of adenylosuccinic acid (ASA), a purine nucleotide cycle metabolite, to stimulate metabolism and buffer skeletal muscle damage in the mdx mouse model of DMD. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were treated with ASA (3000 µg.mL-1) in drinking water. Following the 8-week treatment period, metabolism, mitochondrial density, viability and superoxide (O2-) production, as well as skeletal muscle histopathology, were assessed. ASA treatment significantly improved the histopathological features of murine DMD by reducing damage area, the number of centronucleated fibres, lipid accumulation, connective tissue infiltration and Ca2+ content of mdx tibialis anterior. These effects were independent of upregulated utrophin expression in the tibialis anterior. ASA treatment also increased mitochondrial viability in mdx flexor digitorum brevis fibres and concomitantly reduced O2- production, an effect that was also observed in cultured immortalised human DMD myoblasts. Our data indicates that ASA has a protective effect on mdx skeletal muscles.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Distrofia Muscular Animal/tratamento farmacológico , Monofosfato de Adenosina/uso terapêutico , Animais , Cálcio/análise , Linhagem Celular Transformada , Colágeno/análise , Avaliação Pré-Clínica de Medicamentos , Transporte de Elétrons/efeitos dos fármacos , Humanos , Lipídeos/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular Animal/patologia , Distrofia Muscular de Duchenne/patologia , Mioblastos/metabolismo , Biogênese de Organelas , Consumo de Oxigênio/efeitos dos fármacos , Superóxidos/metabolismo , Utrofina/biossíntese , Utrofina/genética
15.
EBioMedicine ; 52: 102637, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31981975

RESUMO

BACKGROUND: Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb. METHODS: The in vivo blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed in vitro. In silico docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1). FINDINGS: Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by in silico docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution). INTERPRETATION: Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation.


Assuntos
Canagliflozina/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Canagliflozina/química , Ciclo Celular/efeitos dos fármacos , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glutamato Desidrogenase/química , Glutamato Desidrogenase/metabolismo , Humanos , Extremidade Inferior/irrigação sanguínea , Transplante de Células-Tronco Mesenquimais , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Modelos Moleculares , Neovascularização Fisiológica/efeitos dos fármacos , Ligação Proteica , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Relação Estrutura-Atividade
16.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R227-R233, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774307

RESUMO

Doxorubicin (DOX) is a highly effective antineoplastic agent used in cancer treatment. Unfortunately, clinical use of DOX is limited due to the development of dose-dependent toxicity to cardiac and respiratory (i.e., diaphragm) muscles. After administration, DOX preferentially localizes to the inner mitochondrial membrane, where it promotes cellular toxicity via enhanced mitochondrial reactive oxygen species (ROS) production. Although recent evidence suggests that amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following DOX treatment, the mechanisms responsible for this protection remain unknown. Therefore, we tested the hypothesis that DOX-induced mitochondrial ROS production is required to stimulate pathological signaling by the autophagy/lysosomal system (ALS), the ubiquitin-proteasome pathway (UPP), and the unfolded protein response (UPR). Cause and effect were determined by administration of the mitochondria-targeted peptide SS-31 to DOX-treated animals. Interestingly, while SS-31 abrogated aberrant ROS emission in cardiorespiratory muscles of DOX-treated animals, our results revealed muscle-specific regulation of effector pathways. In the heart, SS-31 prevented DOX-induced proteolytic signaling through the ALS and UPP. In contrast, ALS signaling was inhibited by SS-31 in the diaphragm, but the UPP was not affected. UPR signaling was activated in both muscles at eukaryotic translation initiation factor 2α (eIF2α) S51 in the heart and diaphragm of DOX-treated animals and was attenuated with SS-31 treatment in both tissues. However, downstream signaling of eIF2α (activating transcription factor 4 and CCAAT/enhancer-binding protein homologous protein) was diminished in the heart but upregulated in the diaphragm with DOX. Collectively, these results show that DOX-induced ROS production plays distinct roles in the regulation of cardiac and diaphragm muscle proteolysis.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Diafragma/efeitos dos fármacos , Doxorrubicina/toxicidade , Cardiopatias/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Fator 4 Ativador da Transcrição/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Cardiotoxicidade , Diafragma/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Cardiopatias/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Resposta a Proteínas não Dobradas/efeitos dos fármacos
17.
J Ethnopharmacol ; 248: 112326, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31639486

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry (Morus alba L.) leaves have been widely applied to controlling blood glucose as a efficacious traditional Chinese medicine or salutary medical supplement. The extracts of mulberry leaf suppress inflammatory mediators and oxidative stress, protect the pancreatic ß-cells and modulate glucose metabolism in diabetic rats. Our previous studies and others have shown that mulberry leaf extract has excellent therapeutic effects on type 2 diabetes mellitus (T2DM), however, the underlying mechanism remains to be studied. AIM OF THE STUDY: Skeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of T2DM. The aim of this study was to investigate the effects and mechanisms of Mulberry leaf flavonoids (MLF) in L6 skeletal muscle cells and db/db mice. MATERIALS AND METHODS: L6 skeletal muscle cells were cultured and treated with/without MLF for in vitro studies. For in vivo studies, the db/db mice with/without MLF therapy were used. Coomassie brilliant blue staining and α-SMA immunofluorescence staining were used to identify the differentiated L6 cells. Glucose level and ATP level of L6 myotubes were performed by optical density detection and cell viability was performed by MTT method. Mitochondrial membrane potential of L6 myotubes was detected by JC-1 fluorescent staining. ROS level of L6 myotubes was detected by DCFH-DA fluorescent staining. The body weight, food intake, and blood glucose of the mice were measured in different treatment days. Oral glucose tolerance test (OGTT), starch glucose tolerance test (STT) and insulin tolerance test (ITT) were performed in mice. Glycated hemoglobin, glycated serum protein, insulin, liver and muscle glycogen, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) of the mice were detected by corresponding kit. The pathologic change of pancreas and skeletal muscle of mice were performed by H & E staining. Immunohistochemistry staining was used to detect the GLUT4 and p-AMPK expressions in skeletal muscle in mice. GLUT4, CPT-1, NRF1, COXIV, PGC-1α, and p-AMPK expression levels in L6 cells and mice were detected by western bolt assay. RESULTS: MLF and metformin significantly ameliorated muscle glucose uptake and mitochondrial function in L6 muscle cells. MLF also increased the phosphorylation of AMPK and the expression of PGC-1α, and up-regulated the protein levels of m-GLUT4 and T-GLUT4. These effects were reversed by the AMPK inhibitor compound C. In db/db mice, MLF improve diabetes symptoms and insulin resistance. Moreover, MLF elevated the levels of p-AMPK and PGC-1α, raised m-GLUT4 and T-GLUT4 protein expression, and ameliorated mitochondrial function in skeletal muscle of db/db mice. CONCLUSIONS: MLF significantly improved skeletal muscle insulin resistance and mitochondrial function in db/db mice and L6 myocytes through AMPK-PGC-1α signaling pathway, and our findings support the therapeutic effects of MLF on type 2 diabetes.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Resistência à Insulina , Mitocôndrias Musculares/efeitos dos fármacos , Morus , Músculo Esquelético/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Modelos Animais de Doenças , Ativação Enzimática , Flavonoides/isolamento & purificação , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes/isolamento & purificação , Lipídeos/sangue , Masculino , Camundongos , Mitocôndrias Musculares/enzimologia , Morus/química , Músculo Esquelético/enzimologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química
18.
Phytomedicine ; 73: 153038, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378503

RESUMO

BACKGROUND: HCY2, a triterpenoid-enriched extract of Cynomorii Herba, has been shown to reduce body weight and adiposity and attenuate manifestations of the associated metabolic syndrome in high-fat-diet (HFD)-fed mice. PURPOSE: The current study aimed to investigate the biochemical mechanism underlying the anti-obesity effect produced by HCY2. STUDY DESIGN: An HCY2-containing extract was examined for its effects on the regulation of adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma co-activator-1 (PGC1) pathways and the protein expression related to mitochondrial uncoupling and biogenesis in skeletal muscle using an HFD-induced obese mouse model. METHODS: The obese mouse model was produced by providing HFD (60% kcal from fat) ad libitum. The effects and signaling mechanisms of HCY2 were examined using analytical procedures which included enzyme-linked immunosorbent assay kits, Western blot analysis, and the use of a Clark-type oxygen electrode. RESULTS: The current study revealed that the weight reduction produced by HCY2 is associated with the activation of the AMPK signaling pathway, with resultant increases in mitochondrial biogenesis and expression of uncoupling protein 3 in skeletal muscle in vivo. The use of a recoupler, ketocholestanol, delineated the precise role of mitochondrial uncoupling in the anti-obesity effect afforded by HCY2 in obese mice. CONCLUSION: Our experimental findings offer a promising prospect for the use of HCY2 in the management of obesity through the regulation of AMPK/PGC1 pathways.


Assuntos
Fármacos Antiobesidade/farmacologia , Cynomorium/química , Obesidade/tratamento farmacológico , Obesidade/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Fármacos Antiobesidade/química , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos Endogâmicos ICR , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Perda de Peso/efeitos dos fármacos
19.
Artif Organs ; 44(1): 72-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31291698

RESUMO

The effects of liposome-encapsulated hemoglobin with high O2 affinity (h-LEH), an artificial O2 carrier in skeletal muscle, were studied by in situ fatigue resistance test in fast-type plantaris (PLT) and slow-type soleus (SOL) muscles with or without ischemia in the rat. The distal tendons of PLT and SOL muscles were isolated in situ and individually attached to the force transducers to record the developed tension in response to stimuli (80 Hz tetanus train, 1.5 minutes) to the ipsilateral sciatic nerve. The fatigue resistance test (five sets separated by 2-minute rests) was evaluated in terms of tension attenuation (fatigue) from the initial to the last tension (A) during each set, attenuation of the initial (B) or last tension (C) in each set, as compared to the first set in the presence or absence of ischemia or h-LEH (10 mL/kg). While ischemia significantly enhanced fatigue only in PLT, h-LEH showed no effect regardless of the perfusion pattern (normal/ischemia) or muscle-type (PLT/SOL) during each set (A). In parameter (B), set-by-set fatigue development was observed in PLT, whereas h-LEH-SOL showed a trend of advanced fatigue resistance. Such trends became clear in the parameter C (last tension), because h-LEH-SOL exerted, rather than decreased, the tension enhancement regardless of the presence or absence of ischemia, whereas there were no h-LEH effects in PLT. In addition, faster recovery of the nicotinamide adenine dinucleotide content in the muscle after 10 minutes of all fatigue tests was observed in h-LEH-SOL, while saline-SOL still showed a significantly higher value than that of control. These results suggested that additional O2 supply by h-LEH may accelerate the tricarboxylic acid cycle/electron transport chain in slow-type aerobic SOL muscle containing abundant mitochondria and contribute to the faster removal of muscle fatigue substances such as lactate.


Assuntos
Substitutos Sanguíneos/farmacologia , Hemoglobinas/farmacologia , Fadiga Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Animais , Humanos , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/fisiologia , Ratos , Ratos Sprague-Dawley
20.
Am J Physiol Endocrinol Metab ; 318(1): E22-E32, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689144

RESUMO

Factors secreted from tumors/tumor cells are hypothesized to cause skeletal muscle wasting in cancer patients. We examined whether cancer cells secrete factors to promote atrophy by evaluating the effects of conditioned media (CM) from murine lung cancer cells and primary cultures of human lung tumor cells on cultured myotubes. We evaluated murine Lewis lung carcinoma (LLC) and KRASG12D cells, and primary cell lines derived from tumor biopsies from patients with lung cancer (hTCM; n = 6). In all experiments, serum content was matched across treatment groups. We hypothesized that CM from murine and human tumor cells would reduce myotube myosin content, decrease mitochondrial content, and increase mitochondrial reactive oxygen species (ROS) production. Treatment of myotubes differentiated for 7 days with CM from LLC and KRASG12D cells did not alter any of these variables. Effects of murine tumor cell CM were observed when myotubes differentiated for 4 days were treated with tumor cell CM and compared with undiluted differentiation media. However, these effects were not apparent if tumor cell CM treatments were compared with control cell CM or dilution controls. Finally, CM from human lung tumor primary cell lines did not modify myosin content or mitochondrial content or ROS production compared with either undiluted differentiated media, control cell CM, or dilution controls. Our results do not support the hypothesis that factors released from cultured lung cancer/tumor cells promote myotube wasting or mitochondrial abnormalities, but we cannot dismiss the possibility that these cells could secrete such factors in vivo within the native tumor microenvironment.


Assuntos
Caquexia/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Meios de Cultivo Condicionados/farmacologia , Neoplasias Pulmonares/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miosinas/metabolismo , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Caquexia/etiologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Mioblastos Esqueléticos , Neoplasias/complicações , Neoplasias/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas
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