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1.
Life Sci ; 237: 116954, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610192

RESUMO

Sirt3 enzyme and mitochondrial abnormality can be related to excess fatigue or muscular dysfunction in multiple sclerosis (MS).Ellagic acid (EA) has a mitochondrial protector, iron chelator, antioxidant, and axon regenerator in neurons.In this study the effect of EAon muscle dysfunction, its mitochondria, and Sirt3 enzyme incuprizone-induced model of MSwas examined. Demyelination was induced by a diet containing 0.2% w/w cuprizone (Cup) for 42 days and EA administered daily (5, 50, and 100 mg/kg P.O) either with or without cuprizone in mice. Behavioral tests were assessed, and muscle tissue markers ofoxidative stress, mitochondrial parameters, mitochondrial respiratory chain activity, the Sirt3 protein level, and Sirt3 expression were also determined. Luxol fast blue staining and the behavioral tests were performed toassess the implemented model. In Cup group an increased oxidative stress in their muscle tissues was observed. Also, muscle mitochondria exhibited mitochondria dysfunction, lowered mitochondrial respiratory chain activity, Sirt3 protein level, and Sirt3 expression.EA prevented most of these anomalous alterations. Sub-chronicEA co-treatment dose-dependently ameliorated behavioral and muscular impairment in mice that received Cup.EA can effectively protect muscle tissue against cuprizone-induced demeylination via the mitochondrial protection, oxidative stress prevention and Sirt3 overexpression.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/tratamento farmacológico , Ácido Elágico/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Sirtuína 3/metabolismo , Animais , Quelantes/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Estresse Oxidativo/efeitos dos fármacos
2.
Nat Commun ; 10(1): 3923, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462679

RESUMO

Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions. Here we show that NOB significantly improves metabolic fitness in naturally aged mice fed with a regular diet (RD). Furthermore, NOB enhances healthy aging in mice fed with a high-fat diet (HF). In HF skeletal muscle, the NOB-ROR axis broadly activates genes for mitochondrial respiratory chain complexes (MRCs) and fortifies MRC activity and architecture, including Complex II activation and supercomplex formation. These mechanisms coordinately lead to a dichotomous mitochondrial optimization, namely increased ATP production and reduced ROS levels. Together, our study illustrates a focal mechanism by a clock-targeting pharmacological agent to optimize skeletal muscle mitochondrial respiration and promote healthy aging in metabolically stressed mammals.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Flavonas/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/metabolismo , Envelhecimento/metabolismo , Animais , Linhagem Celular , Dieta Hiperlipídica , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo
3.
J Ethnopharmacol ; 242: 112054, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31271820

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside Rg3 from Panax ginseng has reported to have multiple pharmacological activities including anti-diabetics, anti-inflammation and anti-cancer. However, the effect of ginsenoside Rg3 on myogenic differentiation and muscle atrophy is unknown. AIM TO THE STUDY: In this study, we investigated the myogenic effect and underlying molecular mechanisms of ginsenoside Rg3 on myotube atrophy induced by tumor necrosis factor-α (TNF-α). MATERIALS AND METHODS: C2C12 myoblasts were induced to differentiate for one day followed by the treatment of TNF-α along with vehicle or ginsenoside Rg3 for additional 2 days and subjected to immunoblotting, immunocytochemistry, quantitative RT-PCR and biochemical analysis for mitochondrial function. RESULTS: Ginsenoside Rg3 promotes myogenic differentiation and multinucleated myotube formation through Akt activation in a dose-dependent manner, without any cytotoxicity. Ginsenoside Rg3 treatment restores myotube formation and increases myotube diameters under TNF-α-treated conditions. Ginsenoside Rg3 enhances Akt/mTOR (mammalian target of rapamycin) signaling that in turn stimulates muscle-specific gene expression such as myosin heavy chain (MHC) and Myogenin, and suppresses the expression of muscle-specific ubiquitin ligases. In addition, ginsenoside Rg3 in TNF-α-treated myotubes significantly inhibits the production of mitochondrial ROS and restores mitochondrial membrane potential (MMP) and ATP contents. Furthermore, ginsenoside Rg3 upregulates the activities and expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and the mitochondrial biogenetic transcription factors, nuclear respiratory factor-1 (NRF1) and mitochondrial transcription factor A (Tfam) in TNF-α-induced myotube atrophy. CONCLUSIONS: This study provides a mechanistic insight into the effect of ginsenoside Rg3 on myogenic differentiation and myotube atrophy, suggesting that ginsenoside Rg3 has a promising potential as a therapeutic or neutraceutical remedy to intervene muscle weakness and atrophy.


Assuntos
Ginsenosídeos/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias Musculares/fisiologia , Atrofia Muscular , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
4.
Toxicol Mech Methods ; 29(8): 561-568, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31161845

RESUMO

Cleistanthus collinus is a poisonous shrub used for deliberate self-harm in rural areas of South India and intake of boiled decoction of leaves is a common method of self-harm. Distal renal tubular acidosis (dRTA) is an important clinical symptom observed in C. collinus poisoning, and renal V-ATPases may be potential targets of damage. However, a lack of understanding of molecular mediators involved hampers medical management, which is mainly supportive. We hypothesized that C. collinus poisoning induces renal oxidative stress; probably by inducing mitochondrial uncoupling, which compromises V-ATPase activity to ultimately produce dRTA. This was tested by exposing renal BBMV, kidney cells in culture, and Wistar rats to C. collinus poisoning. Exposure to C. collinus aqueous extract resulted in significant elevations in the lipid peroxidation marker, conjugated dienes, in cell culture and in vivo. A significant decrease in mitochondrial respiratory control ratio was observed in kidneys from C. collinus-treated animals suggesting that mitochondrial oxidative phosphorylation is uncoupled. This was accompanied by significant increase in ADP levels and a decrease in proton pump activity. Thus, these results demonstrate that C. collinus poisoning induces oxidative stress which influences proton pump activity, probably due to feedback inhibition by elevated ADP levels because of mitochondrial dysfunction in the rat kidney.


Assuntos
Acidose Tubular Renal/induzido quimicamente , Euphorbiaceae/envenenamento , Rim/efeitos dos fármacos , Mitocôndrias Musculares/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo , Acidose Tubular Renal/metabolismo , Animais , Feminino , Células HEK293 , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Mitocôndrias Musculares/metabolismo , Fosforilação Oxidativa , Extratos Vegetais/envenenamento , Ratos Wistar
6.
Br J Anaesth ; 122(5): 613-621, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30916033

RESUMO

BACKGROUND: Individuals genetically susceptible to malignant hyperthermia (MH) exhibit hypermetabolic reactions when exposed to volatile anaesthetics. Mitochondrial dysfunction has previously been associated with the MH-susceptible (MHS) phenotype in animal models, but evidence of this in human MH is limited. METHODS: We used high resolution respirometry to compare oxygen consumption rates (oxygen flux) between permeabilised human MHS and MH-negative (MHN) skeletal muscle fibres with or without prior exposure to halothane. A substrate-uncoupler-inhibitor titration protocol was used to measure the following components of the electron transport chain under conditions of oxidative phosphorylation (OXPHOS) or after uncoupling the electron transport system (ETS): complex I (CI), complex II (CII), CI+CII and, as a measure of mitochondrial mass, complex IV (CIV). RESULTS: Baseline comparisons without halothane exposure showed significantly increased mitochondrial mass (CIV, P=0.021) but lower flux control ratios in CI+CII(OXPHOS) and CII(ETS) of MHS mitochondria compared with MHN (P=0.033 and 0.005, respectively) showing that human MHS mitochondria have a functional deficiency. Exposure to halothane triggered a hypermetabolic response in MHS mitochondria, significantly increasing mass-specific oxygen flux in CI(OXPHOS), CI+CII(OXPHOS), CI+CII(ETS), and CII(ETS) (P=0.001-0.012), while the rates in MHN samples were unaltered by halothane exposure. CONCLUSIONS: We present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure.


Assuntos
Hipertermia Maligna/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Adolescente , Adulto , Idoso , Anestésicos Inalatórios/farmacologia , Biópsia , Criança , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/fisiologia , Feminino , Predisposição Genética para Doença , Halotano/farmacologia , Humanos , Masculino , Hipertermia Maligna/genética , Hipertermia Maligna/patologia , Pessoa de Meia-Idade , Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-30738211

RESUMO

Acute exposure to crude oil and polycyclic aromatic hydrocarbons (PAH) can severely impair cardiorespiratory function and swim performance of larval, juvenile and adult fish. Interestingly, recent work has documented an oil induced decoupling of swim performance (Ucrit) and maximum metabolic rate (MMR) whereby oil causes a decline in Ucrit without a parallel reduction in MMR. We hypothesize that this uncoupling is due to impaired mitochondrial function in swimming muscles that results in increased proton leak, and thus less ATP generated per unit oxygen. Using high resolution mitochondrial respirometry, we assessed 11 metrics of mitochondrial performance in red and cardiac muscle from permeabilized fibers isolated from red drum following control or 24 h crude oil (high energy water accommodated fractions) exposure. Two experimental series were performed, a Deepwater Horizon relevant low dose (29.6 ±â€¯7.4 µg L-1 ∑PAH50) and a proof-of-concept high dose (64.5 ±â€¯8.9 µg L-1 ∑PAH50). No effects were observed on any mitochondrial parameter in either tissue at the low oil dose; however, high dose exposure provided evidence of impairment in the OXPHOS respiratory control ratio and OXPHOS spare capacity in red muscle following oil exposure, as well as a shift from Complex I to Complex II during OXPHOS respiration. No effects of the high dose oil treatment were observed in cardiac muscle. As such, mitochondrial dysfunction is unlikely to be the underlying mechanism for decoupling of Ucrit and MMR following acute oil exposure in red drum. Furthermore, mitochondrial dysfunction does not appear to be a relevant toxicological impairment in juvenile red drum with respect to the Deepwater Horizon oil spill, although impairments may be observed under higher dose exposure scenarios.


Assuntos
Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Musculares/efeitos dos fármacos , Perciformes , Petróleo/toxicidade , Poluentes Químicos da Água/toxicidade , Envelhecimento , Animais , Larva , Natação
8.
Mol Nutr Food Res ; 63(10): e1801102, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30793867

RESUMO

SCOPE: Oligonol has been shown to moderate mitochondrial biogenesis, protein synthesis, and protein degradation in diabetic mice in a previous study. It is therefore hypothesized that oligonol alleviated sarcopenia by regulating pathways involved in protein turnover and mitochondrial quality. METHODS AND RESULTS: The 32-week-old senescence-accelerated mouse prone 8 (SAMP8) mice are fed with chow diet containing 200 mg kg-1 oligonol for 8 weeks. Oligonol supplementation increased skeletal muscle mass, cross-sectional areas, and grip strength in SAMP8 mice. Oligonol increased phosphorylation of AKT/mTOR/p70sk6, inhibited nuclear localization of FoxO3a and NFκB, and decreased transcription of MuRF-1 and MAFbx in skeletal muscle of SAMP8 mice. Downregulation of mitochondrial biogenesis genes (PGC-1α and Tfam) and mitochondrial fusion genes (Mfn2 and Opa1), loss of PINK1, overexpression of Atg13, LC3-II, and p62, and abundant accumulation of autophagosomes and lysosomes in skeletal muscle of SAMP8 mice are limited by oligonol. Furthermore, oligonol reduced expression of released cytochrome c and cleaved caspase-9 in skeletal muscle of SAMP8 mice. CONCLUSION: Regulating pathways involved in protein synthesis and degradation, mitochondrial biogenesis, mitochondrial fusion/fission, autophagy, and mitochondria-dependent apoptosis by oligonol contribute to positive protein turnover and mitochondrial quality, thus increasing muscle mass and strength in SAMP8 mice.


Assuntos
Catequina/análogos & derivados , Mitocôndrias Musculares/efeitos dos fármacos , Proteínas Musculares/metabolismo , Fenóis/farmacologia , Sarcopenia/tratamento farmacológico , Envelhecimento/fisiologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Catequina/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Camundongos Endogâmicos , Mitocôndrias Musculares/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Musculares/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Sarcopenia/metabolismo , Sarcopenia/patologia
9.
ESC Heart Fail ; 6(2): 328-335, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30688415

RESUMO

AIMS: Elamipretide (ELAM), an aromatic-cationic tetrapeptide, interacts with cardiolipin and normalizes dysfunctional mitochondria of cardiomyocytes. This study examined the effects of ELAM on skeletal muscle mitochondria function in dogs with chronic heart failure (HF). METHODS AND RESULTS: Studies were performed in skeletal muscle biopsy specimens obtained from normal dogs (n = 7) and dogs with chronic intracoronary microembolization-induced HF (n = 14) treated with subcutaneous ELAM 0.5 mg/kg (HF + ELAM, n = 7) or vehicle (normal saline control, HF-CON, n = 7). After 3 months of therapy, triceps skeletal muscle samples were obtained from all dogs, and the proportion of type 1 and type 2 fibres was assessed. Mitochondria isolated from myofibrils of the vastus lateralis skeletal muscle exposed in vitro to ELAM for 1 h were used to assess mitochondrial function. The proportion of skeletal muscle type 1 fibres was lower in HF-CON dogs compared with normal dogs (23 ± 4 vs. 32 ± 5%, P < 0.05). Treatment with ELAM restored a near-normal fibre-type composition (31 ± 7%, P < 0.05 vs. HF-CON). Skeletal muscle mitochondria showed significantly lower levels of adenosine diphosphate-dependent mitochondrial respiration (100 ± 9 vs. 164 ± 15 natom O/min/mg protein, P < 0.05), mitochondrial membrane potential (0.17 ± 0.03 vs. 0.53 ± 0.03 red/green fluorescence ratio, P < 0.05), mitochondrial permeability transition pore (38 ± 3 vs. 62 ± 2 relative light units, P < 0.05), maximum rate of adenosine triphosphate synthesis (3284 ± 418 vs. 8835 ± 423 RLU/µg protein, P < 0.05), and cytochrome c oxidase activity (1390 ± 108 vs. 2459 ± 210 natom O/min/mg protein, P < 0.05) compared with normal dogs. Exposure of skeletal muscle myofibrillar mitochondria from HF dogs to ELAM showed a dose-dependent improvement/normalization of all measures of mitochondrial function. In mitochondria from skeletal muscle of HF dogs exposed to 0.10 µM ELAM, adenosine diphosphate-dependent mitochondrial respiration increased to 183 ± 18 natom O/min/mg protein, membrane potential increased to 0.30 ± 0.03 red/green fluorescence ratio, mitochondrial permeability transition pore increased to 54 ± 4 RLU, maximum rate of adenosine triphosphate synthesis increased to 4423 ± 414, and cytochrome c oxidase activity increased to 2033 ± 191 natom O/min/mg protein. Exposure of skeletal muscle myofibrillar mitochondria from normal dogs to ELAM had no effect on mitochondrial function parameters. CONCLUSIONS: The results indicate that ELAM, previously shown to positively influence mitochondrial function of the failing heart, can also positively impact mitochondrial function of skeletal muscle and potentially help restore skeletal muscle function and improve exercise tolerance.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Actinas/metabolismo , Animais , Biópsia , Western Blotting , Modelos Animais de Doenças , Cães , Insuficiência Cardíaca/fisiopatologia , Injeções Subcutâneas , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Distribuição Aleatória , Volume Sistólico/fisiologia
10.
Gerontology ; 65(3): 240-252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30641518

RESUMO

BACKGROUND: Mitochondrial dysfunction is implicated in the pathogenesis of multiple muscular diseases, including sporadic inclusion body myositis (s-IBM), the most common aging-related muscle disease. However, the factors causing mitochondrial dysfunction in s-IBM are unknown. OBJECTIVE: We hypothesized that resistance exercise (RE) may alleviate muscle impairment by improving mitochondrial function via reducing amyloid-beta (Aß) accumulation. METHODS: Twenty-four male Wistar rats were randomized to a saline-injection control group (sham, n = 8), a chloroquine (CQ) control group (CQ-CON, n = 8), and a CQ plus RE group (CQ-RE, n = 8) in which rats climbed a ladder with weight attached to their tails 9 weeks after starting CQ treatment. RESULTS: RE markedly inhibited soleus muscle atrophy and muscle damage. RE reduced CQ-induced Aß accumulation, which resulted in decreased formation of rimmed vacuoles and mitochondrial-mediated apoptosis. Most importantly, the decreased Aß accumulation improved both mitochondrial quality control (MQC) through increased mitochondrial biogenesis and mitophagy, and mitochondrial dynamics. Furthermore, RE-mediated reduction of Aß accumulation elevated mitochondrial oxidative capacity by upregulating superoxide dismutase-2, catalase, and citrate synthase via activating sirtuin 3 signaling. CONCLUSION: RE enhances mitochondrial function by improving MQC and mitochondrial oxidative capacity via reducing Aß accumulation, thereby inhibiting CQ-induced muscle impairment, in a rat model of s-IBM.


Assuntos
Miosite de Corpos de Inclusão/terapia , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose , Catalase/metabolismo , Cloroquina/toxicidade , Citrato (si)-Sintase/metabolismo , Modelos Animais de Doenças , Geriatria , Humanos , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/fisiopatologia , Condicionamento Físico Animal , Ratos , Ratos Wistar , Treinamento de Resistência , Superóxido Dismutase/metabolismo
11.
Circulation ; 139(11): 1422-1434, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30612451

RESUMO

BACKGROUND: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. METHODS: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. RESULTS: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P=0.01) and increased sedentary time ( P=0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Pparγ, in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. CONCLUSIONS: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Ácidos Graxos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fosfatos/efeitos adversos , Fósforo na Dieta/efeitos adversos , Animais , Linhagem Celular , Metabolismo Energético/genética , Exercício , Tolerância ao Exercício/genética , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Fosfatos/administração & dosagem , Fosfatos/metabolismo , Fósforo na Dieta/administração & dosagem , Fósforo na Dieta/metabolismo , Comportamento Sedentário
12.
J Cell Physiol ; 234(2): 1643-1658, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30132871

RESUMO

Sarcopenia, which refers to the muscle loss that accompanies aging, is a complex neuromuscular disorder with a clinically high prevalence and mortality. Despite many efforts to protect against muscle weakness and muscle atrophy, the incidence of sarcopenia and its related permanent disabilities continue to increase. In this study, we found that treatment with human placental hydrolysate (hPH) significantly increased the viability (approximately 15%) of H2 O2 -stimulated C2C12 cells. Additionally, while H2 O2 -stimulated cells showed irregular morphology, hPH treatment restored their morphology to that of cells cultured under normal conditions. We further showed that hPH treatment effectively inhibited H2 O2 -induced cell death. Reactive oxygen species (ROS) generation and Mstn expression induced by oxidative stress are closely associated with muscular dysfunction followed by atrophy. Exposure of C2C12 cells to H2 O2 induced abundant production of intracellular ROS, mitochondrial superoxide, and mitochondrial dysfunction as well as myostatin expression via nuclear factor-κB (NF-κB) signaling; these effects were attenuated by hPH. Additionally, hPH decreased mitochondria fission-related gene expression (Drp1 and BNIP3) and increased mitochondria biogenesis via the Sirt1/AMPK/PGC-1α pathway and autophagy regulation. In vivo studies revealed that hPH-mediated prevention of atrophy was achieved predominantly through regulation of myostatin and PGC-1α expression and autophagy. Taken together, our findings indicate that hPH is potentially protective against muscle atrophy and oxidative cell death.


Assuntos
Antioxidantes/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Placenta , Extratos de Tecidos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Pelados , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miostatina/metabolismo , NF-kappa B/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Gravidez
13.
Environ Sci Pollut Res Int ; 26(3): 2375-2386, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30467749

RESUMO

In the past few years, polychlorinated biphenyls (PCBs), a class of environmental pollutants, have been associated with metabolism dysregulation. Muscle is one of the key regulators of metabolism because of its mass and its important role in terms of glucose consumption and glucose storage. It has been shown that muscle alterations, such as oxidative stress and mitochondrial dysfunction, contribute significantly to the development of metabolic diseases. No study has yet investigated the toxicological effect of PCBs on muscle mitochondrial function and oxidative stress in vivo. The aim of this study was to assess the effect of PCB126 in vivo exposure (single dose of 1.05 µmol/kg) on muscle mitochondrial function and oxidative stress in rats. PCB126-treated rats showed a marked increase in Cyp1a1 mRNA levels in skeletal muscles in association with a 40% reduction in state 3 oxygen consumption rate measured with complex I substrates in permeabilized muscle fibers. Furthermore, PCB126 exposure altered the expression of some enzymes involved in ROS detoxification such as catalase and glutaredoxin 2. Our results highlight for the first time a toxic effect of coplanar PCBs on skeletal muscle mitochondrial function and oxidative stress. This suggests that acute PCB exposure, by affecting muscle metabolism, could contribute to the development of metabolic disorders. Studies are needed to determine if lower-level but longer-term PCB exposure exhibits the same effect.


Assuntos
Mitocôndrias Musculares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Animais , Catalase/genética , Catalase/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Poluentes Ambientais/toxicidade , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Inativação Metabólica/efeitos dos fármacos , Inativação Metabólica/genética , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Oxigênio/metabolismo , Ratos Sprague-Dawley
14.
Metabolism ; 91: 1-9, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30445139

RESUMO

AIMS/HYPOTHESIS: In this study, we aimed to examine real-time effects of molecules released by contracting skeletal muscle on the insulin secretory function of ß-cells using a novel perifusion platform. We hypothesised that media conditioned by contracting skeletal muscle will influence insulin secretion and mitochondrial energy metabolism in ß-cells under normal and type-2 diabetic conditions. METHODS: INS-1 832/3 pseudoislets were perifused with media from C2C12 myotubes treated with or without electrical pulse stimulation (EPS; 40 V, 1.0 Hz, 2 ms). Insulin secretory function of pseudoislets was measured before, during, and after EPS to simulate pre-, during-, and post-exercise like effects. Additional experiments were completed in INS-1 832/3 cells under "healthy" and "diabetic-like" conditions as well as human pancreatic islets isolated from nondiabetic and type 2 diabetic donors. RESULTS: Insulin secretion increased significantly (P < 0.05) by pseudoislets when perifused with media from myotubes treated with but not without EPS. Conditioned media from EPS-treated myotubes also potentiated insulin secretion from INS-1 832/3 cell monolayers in the presence (P < 0.05) and absence of palmitate (P < 0.001) and in nondiabetic (P < 0.01) and type-2 diabetic (P = 0.06) isolated human islets. Pre-treatment of INS-1 832/3 cells to 24-hour high glucose ±â€¯palmitate dampened this effect. Moreover, conditioned media from myotubes treated with EPS significantly increased mitochondrial respiratory activity of INS-1 832/3 cells. CONCLUSION/INTERPRETATION: Conditioned media from myotubes treated with EPS potentiates acute insulin release from normal cultured ß-cells, nondiabetic islets and Type-2 diabetic islets and is associated with enhanced mitochondrial substrate oxidation.


Assuntos
Meios de Cultivo Condicionados/farmacologia , Metabolismo Energético/efeitos dos fármacos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/química , Células Cultivadas , Meios de Cultivo Condicionados/química , Diabetes Mellitus Tipo 2/metabolismo , Estimulação Elétrica , Feminino , Glucose/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/efeitos dos fármacos , Contração Muscular , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Consumo de Oxigênio/efeitos dos fármacos
15.
J Physiol Sci ; 69(2): 327-333, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30536041

RESUMO

Statins and exercise reduce cardiovascular disease incidence. We investigated whether endurance exercise in mice induces mitochondrial adaptation in skeletal muscle and muscle injury during administration of atorvastatin, a member of the statin medication class. Male C57BL mice were assigned to one of three groups: control (Con), statin (Statin), or statin and exercise (Statin + Ex). Atorvastatin was administered, and exercise performed on a treadmill for 8 weeks. The levels of mitochondria-associated proteins, PGC-1α, and respiratory chain complex, (COX) I-V, in the quadriceps femoris, and serum creatine kinase, a muscle injury marker, were measured. PGC-1α and COX I-V were upregulated in the Statin + Ex group compared to those in the Statin and Con groups; serum creatine kinase levels were similar. Endurance training in mice induced mitochondrial adaptation in skeletal muscle without causing muscle injury, during atorvastatin administration.


Assuntos
Atorvastatina/farmacologia , Transporte de Elétrons/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Condicionamento Físico Animal/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Animais , Creatina Quinase/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Quadríceps/efeitos dos fármacos , Músculo Quadríceps/metabolismo
16.
EMBO J ; 38(1)2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30420558

RESUMO

As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids. The metabolic lipid imbalance can be traced to an altered fatty acid synthesis and fatty acid oxidation, accompanied by a defect in acyl chain elongation and desaturation. As an underlying cause, we reveal a severe sarcoplasmic reticulum (SR) stress, leading to the activation of the lipogenic SREBP1c/SREBP2 factors, the accumulation of the Fgf21 cytokine, and alterations of SR-mitochondria morphology. Importantly, pharmacological treatments with the chaperone TUDCA and the fatty acid oxidation activator bezafibrate improve muscle histology and strength of lipin1 mutants. Our data reveal that SR stress and alterations in SR-mitochondria contacts are contributing factors and potential intervention targets of the myopathy associated with lipin1 deficiency.


Assuntos
Estresse do Retículo Endoplasmático/genética , Doenças Musculares/genética , Fosfatidato Fosfatase/genética , Retículo Sarcoplasmático/metabolismo , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Chaperonas Moleculares/farmacologia , Chaperonas Moleculares/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/tratamento farmacológico , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/patologia , Ácido Tauroquenodesoxicólico/uso terapêutico
17.
Mol Nutr Food Res ; 63(6): e1800649, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30575271

RESUMO

SCOPE: This study investigates the dual actions of 6-gingerol in stimulating both plasma adiponectin and muscular adiponectin receptor signaling in naturally ageing rats. METHODS AND RESULTS: Twenty-two-month-old male SD rats were treated with 6-gingerol (0.2 mg kg-1 , once daily) for 7 weeks. 6-Gingerol can attenuate age-associated high plasma triglyceride, glucose, and insulin concentrations under fasting conditions as well as suppress the increase in the HOMA-IR index and inhibit the decrease of muscular p-Akt/Akt protein in ageing rats, which indicates an improvement of systemic and muscular insulin sensitivity. Accompanying these changes, treatment with 6-gingerol attenuates excessive triglyceride accumulation, enhances mitochondrial function, and promotes a transition from a fast- to slow-fiber type and muscle oxidative metabolism in the red gastrocnemius of ageing rats. More importantly, 6-gingerol not only increases the plasma and adipose tissue adiponectin concentrations, but also elevates muscular AdipoR1 expression and activates downstream AMPK phosphorylation as well as upregulates PGC-1α in vivo and in vitro. CONCLUSION: 6-Gingerol may improve ectopic lipid accumulation, mitochondrial dysfunction, and insulin resistance in skeletal muscle of ageing rats. These effects rely, at least in part, on the elevated plasma adiponectin concentration and muscle AdipoR1 level to dually activate the AMPK/PGC-1α signaling pathway.


Assuntos
Envelhecimento/fisiologia , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/sangue , Envelhecimento/efeitos dos fármacos , Animais , Resistência à Insulina , Masculino , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Ácido Oleico/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Exp Physiol ; 104(3): 306-321, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30578638

RESUMO

NEW FINDINGS: What is the central question of this study? What are the temporal responses of mitochondrial respiration and mitochondrial responsivity to insulin in soleus muscle fibres from mice during the development of obesity and insulin resistance? What is the main finding and its importance? Short- and long-term feeding with a high-fat diet markedly reduced soleus mitochondrial respiration and mitochondrial responsivity to insulin before any change in glycogen synthesis. Muscle glycogen synthesis and whole-body insulin resistance were present after 14 and 28 days, respectively. Our findings highlight the plasticity of mitochondria during the development of obesity and insulin resistance. ABSTRACT: Recently, significant attention has been given to the role of muscle mitochondrial function in the development of insulin resistance associated with obesity. Our aim was to investigate temporal alterations in mitochondrial respiration, H2 O2 emission and mitochondrial responsivity to insulin in permeabilized skeletal muscle fibres during the development of obesity in mice. Male Swiss mice (5-6 weeks old) were fed with a high-fat diet (60% calories from fat) or standard diet for 7, 14 or 28 days to induce obesity and insulin resistance. Diet-induced obese (DIO) mice presented with reduced glucose tolerance and hyperinsulinaemia after 7 days of high-fat diet. After 14 days, the expected increase in muscle glycogen content after systemic injection of glucose and insulin was not observed in DIO mice. At 28 days, blood glucose decay after insulin injection was significantly impaired. Complex I (pyruvate + malate) and II (succinate)-linked respiration and oxidative phosphorylation (ADP) were decreased after 7 days of high-fat diet and remained low in DIO mice after 14 and 28 days of treatment. Moreover, mitochondria from DIO mice were incapable of increasing respiratory coupling and ADP responsivity after insulin stimulation in all observed periods. Markers of mitochondrial content were reduced only after 28 days of treatment. The mitochondrial H2 O2 emission profile varied during the time course of DIO, with a reduction of H2 O2 emission in the early stages of DIO and an increased emission after 28 days of treatment. Our data demonstrate that DIO promotes transitory alterations in mitochondrial physiology during the early and late stages of insulin resistance related to obesity.


Assuntos
Respiração Celular/efeitos dos fármacos , Insulina/farmacologia , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Obesidade/fisiopatologia , Descanso/fisiologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos
19.
Oxid Med Cell Longev ; 2018: 8936251, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30473743

RESUMO

Aging skeletal muscles are characterized by a progressive decline in muscle mass and muscular strength. Such muscular dysfunctions are usually associated with structural and functional alterations of skeletal muscle mitochondria. The senescence-accelerated mouse-prone 8 (SAMP8) model, characterized by premature aging and high degree of oxidative stress, was used to investigate whether a combined intervention with mild physical exercise and ubiquinol supplementation was able to improve mitochondrial function and preserve skeletal muscle health during aging. 5-month-old SAMP8 mice, in a presarcopenia phase, have been randomly divided into 4 groups (n = 10): untreated controls and mice treated for two months with either physical exercise (0.5 km/h, on a 5% inclination, for 30 min, 5/7 days per week), ubiquinol 10 (500 mg/kg/day), or a combination of exercise and ubiquinol. Two months of physical exercise significantly increased mitochondrial damage in the muscles of exercised mice when compared to controls. On the contrary, ubiquinol and physical exercise combination significantly improved the overall status of the skeletal muscle, preserving mitochondrial ultrastructure and limiting mitochondrial depolarization induced by physical exercise alone. Accordingly, combination treatment while promoting mitochondrial biogenesis lowered autophagy and caspase 3-dependent apoptosis. In conclusion, the present study shows that ubiquinol supplementation counteracts the deleterious effects of physical exercise-derived ROS improving mitochondrial functionality in an oxidative stress model, such as SAMP8 in the presarcopenia phase.


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/terapia , Ubiquinona/análogos & derivados , Animais , Autofagia/efeitos dos fármacos , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Doenças Mitocondriais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico
20.
J Stroke Cerebrovasc Dis ; 27(11): 3342-3344, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30181037

RESUMO

Botulinum neurotoxin injection therapy and rehabilitation have been conducted for stroke patients to reduce the spasticity of their affected limbs and improve their walking ability and daily living. Furthermore, their disability was reported to be related to muscle wasting. Supplementation of l-carnitine was reported to improve physical endurance and was used to treat sarcopenia in, for example, patients with cancer. Here, we report a case of chronic stroke with muscle wasting in a patient with improved walking endurance by l-carnitine supplementation, botulinum neurotoxin injection, and rehabilitation. A 58-year-old woman had a left putamen hemorrhage 9years before, and right spastic hemiplegia and walking disability. She could walk no more than 20m. Botulinum neurotoxin injection and rehabilitation were performed 6times every 3 months. The first time, walking speed and continuous walking distance increased as her spasticity decreased. However, the improvement declined after the second and third treatments. She had right leg pain during walking, accompanied by muscle wasting. The l-carnitine prescription contributed to the attenuation of her leg pain during walking and rapid improvement of her continuous walking distance. Walking speed and endurance further improved. In addition, the withdrawal of l-carnitine did not decrease her walking ability or induce a recurrence of her leg pain. Interestingly, creatine phosphokinase increased after l-carnitine was stopped, indicating that l-carnitine had helped to reduce muscle damage during rehabilitation. This case suggests that chronic stroke patients with muscle wasting have an abnormality in the mitochondrial energy metabolism of their muscles.


Assuntos
Inibidores da Liberação da Acetilcolina/administração & dosagem , Toxinas Botulínicas/administração & dosagem , Carnitina/administração & dosagem , Suplementos Nutricionais , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Caminhada , Terapia Combinada , Avaliação da Deficiência , Metabolismo Energético/efeitos dos fármacos , Tolerância ao Exercício , Feminino , Marcha , Humanos , Injeções , Pessoa de Meia-Idade , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Atrofia Muscular/diagnóstico , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
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