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1.
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
2.
Nat Commun ; 12(1): 470, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473109

RESUMO

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.


Assuntos
Envelhecimento/genética , Homeostase/fisiologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Adulto , Animais , Linhagem Celular , Núcleo Celular , Regulação da Expressão Gênica , Humanos , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mioblastos/metabolismo , Estresse Fisiológico , Adulto Jovem
3.
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
4.
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
5.
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
6.
Sci Rep ; 10(1): 21811, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311521

RESUMO

The present study was conducted to estimate the effects of dietary carbohydrates on muscle quality and the underlying mechanisms. Six isonitrogenous and isolipidic diets were formulated to contain graded levels of carbohydrates (0%, 8%, 12%, 16%, 20% and 24%, respectively). These diets were named as C0, C8, C12, C16, C20 and C24, respectively. After a 10-week feeding trial, results showed that the muscle pH, liquid holding capacity (LHC) and hardness were significantly decreased by the increasing dietary carbohydrate levels. Dietary carbohydrates significantly decreased the muscle fibre diameter, and the highest value was found in the C0 group. Accumulated glycogen and degenerated mitochondrial cristae were observed in the C24 group. Significantly higher contents of protein carbonyls were observed in the C20 group and C24 group (P < 0.05). There was a significant decrease of mtDNA copy number in the C24 group compared with that in the C0 and C8 groups. The AMP/ATP ratio in muscle decreased first and then increased with the increasing dietary carbohydrate levels. The dietary incorporation of carbohydrate significantly reduced the expression of opa1, pygm and genes involved in myogenesis (myf5 and myog). Meanwhile, proteolysis-related genes (murf-1, mafbx, capn2 and ctsl), pro-inflammatory cytokines (il-6 and tnf-α) and mstn were significantly up-regulated. In the C24 group, significant increase of phosphorylation of AMPK (Thr172), up-regulation of PGC-1α and GLUT4 were observed, while the phosphorylation level of S6 (Ser235/236) was significantly decreased. It was concluded that excessive dietary carbohydrate level (24%) had negative impacts on mitochondria function and promoted glycogen accumulation, and thereafter influenced the muscle quality of olive flounder. The activation of AMPK as well as the upregulation of PGC-1α and GLUT4 was the key mechanism.


Assuntos
Ração Animal , Carboidratos da Dieta/farmacologia , Proteínas de Peixes/metabolismo , Linguado/metabolismo , Glicogênio/metabolismo , Mitocôndrias Musculares/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Animais
7.
Int J Mol Sci ; 22(1)2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374852

RESUMO

Sarcopenia is a chronic disease characterized by the progressive loss of skeletal muscle mass, force, and function during aging. It is an emerging public problem associated with poor quality of life, disability, frailty, and high mortality. A decline in mitochondria quality control pathways constitutes a major mechanism driving aging sarcopenia, causing abnormal organelle accumulation over a lifetime. The resulting mitochondrial dysfunction in sarcopenic muscles feedbacks systemically by releasing the myomitokines fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), influencing the whole-body homeostasis and dictating healthy or unhealthy aging. This review describes the principal pathways controlling mitochondrial quality, many of which are potential therapeutic targets against muscle aging, and the connection between mitochondrial dysfunction and the myomitokines FGF21 and GDF15 in the pathogenesis of aging sarcopenia.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Renovação Mitocondrial , Sarcopenia/metabolismo , Animais , Humanos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Músculo Esquelético/metabolismo , Sarcopenia/patologia
8.
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
9.
Exerc Sport Sci Rev ; 48(4): 180-187, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32658044

RESUMO

Low-load blood flow restricted resistance exercise (BFRRE) can stimulate whole-muscle growth and improve muscle function. However, limited knowledge exists on the effects at the myocellular level. We hypothesize that BFRRE has the ability to produce concurrent skeletal muscle myofibrillar, mitochondrial, and microvascular adaptations, thus offering an alternative strategy to counteract decay in skeletal muscle health and function in clinical populations.


Assuntos
Adaptação Fisiológica , Microcirculação/fisiologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/irrigação sanguínea , Miofibrilas/fisiologia , Treinamento de Resistência/métodos , Humanos , Proteínas Musculares/biossíntese , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/fisiologia , Consumo de Oxigênio , Fluxo Sanguíneo Regional
10.
Food Chem ; 328: 127174, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32492604

RESUMO

This study investigated the effect of lysosomal iron involvement in the mechanism of mitochondrial apoptosis on bovine muscle protein degradation during postmortem aging. Six crossbred cattle were studied to evaluate intracellular reactive oxygen species (ROS), antioxidant enzyme activity, lysosomal membrane stability, mitochondrial dysfunction-induced apoptosis, desmin and troponin-T degradation in both control and iron chelator desferrioxamine (DFO) groups. Results showed that lysosomal iron induced ROS accumulation and lysosomal membrane destabilization by decreasing the antioxidant enzyme activity (P < 0.05). Subsequently, lysosomal dysfunction mediated by iron increased mitochondrial membrane permeability and decreased mitochondrial membrane potential, thereby enhancing Bid and cytochrome c release and caspase-9/-3 activation (P < 0.05). Ultimately, lysosomal iron mediated lysosomal-mitochondrial apoptosis increased the postmortem bovine muscle desmin and troponin-T degradation (P < 0.05). The results indicated that lysosomal iron contributes to postmortem meat tenderization through the lysosomal-mitochondrial dysfunction-induced apoptosis pathway.


Assuntos
Ferro/metabolismo , Lisossomos/metabolismo , Proteínas de Carne/metabolismo , Mitocôndrias Musculares/patologia , Membranas Mitocondriais/patologia , Animais , Apoptose/efeitos dos fármacos , Autopsia , Bovinos , Permeabilidade da Membrana Celular , Citocromos c/metabolismo , Masculino , Mitocôndrias/metabolismo , Mitocôndrias Musculares/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Musculares/metabolismo , Proteólise , Espécies Reativas de Oxigênio/metabolismo
11.
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
12.
Mol Cell ; 79(4): 575-587.e7, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32589965

RESUMO

eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/- mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health.


Assuntos
Fator de Iniciação 3 em Eucariotos/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Elongação Traducional da Cadeia Peptídica , Animais , Membrana Celular/genética , Membrana Celular/metabolismo , Fator de Iniciação 3 em Eucariotos/genética , Células HeLa , Humanos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Subunidades Ribossômicas/genética , Subunidades Ribossômicas/metabolismo
13.
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
14.
Science ; 368(6490)2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355002

RESUMO

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand-an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-/- mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.


Assuntos
Adaptação Fisiológica/imunologia , Glicogênio/metabolismo , Interleucina-13/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Resistência Física/imunologia , Animais , Glicemia/metabolismo , Linhagem Celular , Ácidos Graxos/metabolismo , Feminino , Humanos , Interleucina-13/sangue , Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mioblastos/metabolismo , Oxirredução , Condicionamento Físico Animal , Corrida , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
15.
Am J Physiol Endocrinol Metab ; 319(1): E187-E195, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32396388

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and impaired insulin sensitivity. Reduced hepatic ketogenesis may promote these pathologies, but data are inconclusive in humans and the link between NAFLD and reduced insulin sensitivity remains obscure. We investigated individuals with obesity-related NAFLD and hypothesized that ß-hydroxybutyrate (ßOHB; the predominant ketone species) would be reduced and related to hepatic fat accumulation and insulin sensitivity. Furthermore, we hypothesized that ketones would impact skeletal muscle mitochondrial respiration in vitro. Hepatic fat was assessed by 1H-MRS in 22 participants in a parallel design, case control study [Control: n = 7, age 50 ± 6 yr, body mass index (BMI) 30 ± 1 kg/m2; NAFLD: n = 15, age 57 ± 3 yr, BMI 35 ± 1 kg/m2]. Plasma assessments were conducted in the fasted state. Whole body insulin sensitivity was determined by the gold-standard hyperinsulinemic-euglycemic clamp. The effect of ketone dose (0.5-5.0 mM) on mitochondrial respiration was conducted in human skeletal muscle cell culture. Fasting ßOHB, a surrogate measure of hepatic ketogenesis, was reduced in NAFLD (-15.6%, P < 0.01) and correlated negatively with liver fat (r2 = 0.21, P = 0.03) and positively with insulin sensitivity (r2 = 0.30, P = 0.01). Skeletal muscle mitochondrial oxygen consumption increased with low-dose ketones, attributable to increases in basal respiration (135%, P < 0.05) and ATP-linked oxygen consumption (136%, P < 0.05). NAFLD pathophysiology includes impaired hepatic ketogenesis, which is associated with hepatic fat accumulation and impaired insulin sensitivity. This reduced capacity to produce ketones may be a potential link between NAFLD and NAFLD-associated reductions in whole body insulin sensitivity, whereby ketone concentrations impact skeletal muscle mitochondrial respiration.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Fígado/metabolismo , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Ácidos Graxos não Esterificados/metabolismo , Feminino , Técnica Clamp de Glucose , Humanos , Técnicas In Vitro , Resistência à Insulina , Corpos Cetônicos/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Espectroscopia de Prótons por Ressonância Magnética
16.
Am J Physiol Endocrinol Metab ; 319(1): E67-E80, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32396498

RESUMO

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower hindlimb oxygen consumption rates (OCRs), indicating depressed mitochondrial oxidative phosphorylation capacity in their skeletal muscle. We hypothesized that OCRs are lower in skeletal muscle mitochondria from IUGR fetuses, due to reduced electron transport chain (ETC) activity and lower abundances of tricarboxylic acid (TCA) cycle enzymes. IUGR sheep fetuses (n = 12) were created with mid-gestation maternal hyperthermia and compared with control fetuses (n = 12). At 132 ± 1 days of gestation, biceps femoris muscles were collected, and the mitochondria were isolated. Mitochondria from IUGR muscle have 47% lower State 3 (Complex I-dependent) OCRs than controls, whereas State 4 (proton leak) OCRs were not different between groups. Furthermore, Complex I, but not Complex II or IV, enzymatic activity was lower in IUGR fetuses compared with controls. Proteomic analysis (n = 6/group) identified 160 differentially expressed proteins between groups, with 107 upregulated and 53 downregulated mitochondria proteins in IUGR fetuses compared with controls. Although no differences were identified in ETC subunit protein abundances, abundances of key TCA cycle enzymes [isocitrate dehydrogenase (NAD+) 3 noncatalytic subunit ß (IDH3B), succinate-CoA ligase ADP-forming subunit-ß (SUCLA2), and oxoglutarate dehydrogenase (OGDH)] were lower in IUGR mitochondria. IUGR mitochondria had a greater abundance of a hypoxia-inducible protein, NADH dehydrogenase 1α subcomplex 4-like 2, which is known to incorporate into Complex I and lower Complex I-mediated NADH oxidation. Our findings show that mitochondria from IUGR skeletal muscle adapt to hypoxemia and hypoglycemia by lowering Complex I activity and TCA cycle enzyme concentrations, which together, act to lower OCR and NADH production/oxidation in IUGR skeletal muscle.


Assuntos
Ciclo do Ácido Cítrico/fisiologia , Complexo I de Transporte de Elétrons/metabolismo , Retardo do Crescimento Fetal/metabolismo , Mitocôndrias Musculares/metabolismo , Animais , Regulação para Baixo , Complexo II de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Retardo do Crescimento Fetal/enzimologia , Músculos Isquiossurais/enzimologia , Músculos Isquiossurais/metabolismo , Hipoglicemia/enzimologia , Hipoglicemia/metabolismo , Hipóxia/enzimologia , Hipóxia/metabolismo , Isocitrato Desidrogenase/metabolismo , Complexo Cetoglutarato Desidrogenase/metabolismo , Mitocôndrias Musculares/enzimologia , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Insuficiência Placentária/enzimologia , Insuficiência Placentária/metabolismo , Gravidez , Proteômica , Ovinos , Succinato-CoA Ligases/metabolismo , Regulação para Cima
17.
Int J Sports Med ; 41(10): 633-645, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32455453

RESUMO

Biology is rich in claims that reactive oxygen and nitrogen species are involved in every biological process and disease. However, many quantitative aspects of redox biology remain elusive. The important quantitative parameters you need to address the feasibility of redox reactions in vivo are: rate of formation and consumption of a reactive oxygen and nitrogen species, half-life, diffusibility and membrane permeability. In the first part, we explain the basic chemical kinetics concepts and algebraic equations required to perform "street fighting" quantitative analysis. In the second part, we provide key numbers to help thinking about sizes, concentrations, rates and other important quantities that describe the major oxidants (superoxide, hydrogen peroxide, nitric oxide) and antioxidants (vitamin C, vitamin E, glutathione). In the third part, we present the quantitative effect of exercise on superoxide, hydrogen peroxide and nitric oxide concentration in mitochondria and whole muscle and calculate how much hydrogen peroxide concentration needs to increase to transduce signalling. By taking into consideration the quantitative aspects of redox biology we can: i) refine the broad understanding of this research area, ii) design better future studies and facilitate comparisons among studies, and iii) define more efficiently the "borders" between cellular signaling and stress.


Assuntos
Exercício Físico/fisiologia , Condicionamento Físico Humano/fisiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Oxirredução , Estresse Oxidativo , Transdução de Sinais
18.
Exerc Sport Sci Rev ; 48(3): 119-124, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32271180

RESUMO

Blood lactate concentrations traditionally have been used as an index of exercise intensity or clinical hyperlactatemia. However, more recent data suggest that fasting plasma lactate can also be indicative of the risk for subsequent metabolic disease. The hypothesis presented is that fasting blood lactate accumulation reflects impaired mitochondrial substrate use, which in turn influences metabolic disease risk.


Assuntos
Ácido Láctico/sangue , Síndrome Metabólica/sangue , Biomarcadores/sangue , Ciclo do Ácido Cítrico , Diabetes Mellitus Tipo 2/sangue , Jejum , Humanos , Síndrome Metabólica/diagnóstico , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Obesidade/sangue , Fatores de Risco
19.
Am J Chin Med ; 48(3): 631-650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329640

RESUMO

The loss of skeletal muscle mass and function is a serious consequence of chronic diseases and aging. BST204 is a purified ginseng (the root of Panax ginseng) extract that has been processed using ginsenoside-ß-glucosidase and acid hydrolysis to enrich ginsenosides Rg3 and Rh2 from the crude ginseng. BST204 has a broad range of health benefits, but its effects and mechanism on muscle atrophy are currently unknown. In this study, we have examined the effects and underlying mechanisms of BST204 on myotube formation and myotube atrophy induced by tumor necrosis factor-α (TNF-α). BST204 promotes myogenic differentiation and multinucleated myotube formation through Akt activation. BST204 prevents myotube atrophy induced by TNF-α through the activation of Akt/mTOR signaling and down-regulation of muscle-specific ubiquitin ligases, MuRF1, and Atrogin-1. Furthermore, BST204 treatment in atrophic myotubes suppresses mitochondrial reactive oxygen species (ROS) production and regulates mitochondrial transcription factors such as NRF1 and Tfam, through enhancing the activity and expression of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Collectively, our findings indicate that BST204 improves myotube formation and PGC1α-mediated mitochondrial function, suggesting that BST204 is a potential therapeutic or neutraceutical remedy to intervene muscle weakness and atrophy.


Assuntos
Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Panax/química , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Atrofia/induzido quimicamente , Atrofia/tratamento farmacológico , Humanos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estimulação Química , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa
20.
Sci Rep ; 10(1): 6095, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269244

RESUMO

The common clinical symptoms of Friedreich's ataxia (FRDA) include ataxia, muscle weakness, type 2 diabetes and heart failure, which are caused by impaired mitochondrial function due to the loss of frataxin (FXN) expression. Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on FRDA has not been studied. Here we found that mice with genetic knockout and knock-in of the Fxn gene (KIKO mice) developed exercise intolerance, glucose intolerance and moderate cardiac dysfunction at 6 months of age. These abnormalities were associated with impaired mitochondrial respiratory function concurrent with reduced iron regulatory protein 1 (Irp1) expression as well as increased oxidative stress, which were not due to loss of mitochondrial content and antioxidant enzyme expression. Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.


Assuntos
Ataxia de Friedreich/prevenção & controle , Condicionamento Físico Animal/métodos , Corrida , Animais , Ataxia de Friedreich/genética , Ataxia de Friedreich/fisiopatologia , Proteína 1 Reguladora do Ferro/genética , Proteína 1 Reguladora do Ferro/metabolismo , Proteínas de Ligação ao Ferro/genética , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Estresse Oxidativo
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