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1.
Am J Physiol Endocrinol Metab ; 320(4): E680-E690, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33554779

RESUMO

Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, whereas MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.NEW & NOTEWORTHY MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.


Assuntos
Proteínas Mitocondriais/fisiologia , Atrofia Muscular/metabolismo , Miostatina/sangue , Miostatina/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Dieta Hiperlipídica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas Mitocondriais/sangue , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/sangue , Atrofia Muscular/etiologia , Miostatina/metabolismo , Ácido Palmítico , Transdução de Sinais/fisiologia , Adulto Jovem
2.
Toxicol Appl Pharmacol ; 348: 1-13, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29653124

RESUMO

Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor.At cells were treated with 0.5 or 1 µM DOX for 24 h, and morphological, functional and biochemical changes associated with mitochondrial bioenergetics, DNA-damage response and apoptosis were measured. Both DOX concentrations decreased ATP levels and SOD2 protein levels and induced p53-dependent caspase activation. However, differential effects were observed for the two DOX concentrations. The highest concentration induced a high degree of apoptosis, with increased nuclear apoptotic morphology, PARP-1 cleavage and decrease of some OXPHOS protein subunits. At the lowest concentration, DOX increased the expression of p53 target transcripts associated with mitochondria-dependent apoptosis and decreased transcripts related with DNA-damage response and glycolysis. Interestingly, cells treated with 0.5 µM DOX presented an increase in PDK4 transcript levels, accompanied by an increase in phospho-PDH and decreased PDH activity. This was accompanied by an apparent decrease in basal and maximal oxygen consumption rates (OCR) and in basal extracellular acidification rate (ECAR). Cells pre-treated with the PDK inhibitor dichloroacetate (DCA), with the aim of restoring PDH activity, partially recovered OCR and ECAR. The results suggest that the higher DOX concentration mainly induces p53-dependent apoptosis, whereas for the lower DOX concentration the cardiotoxic effects involve bioenergetic failure, unveiling PDH as a possible therapeutic target to decrease DOX cardiotoxicity.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Metabolismo Energético/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Diferenciação Celular , Linhagem Celular , Dano ao DNA , Relação Dose-Resposta a Droga , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Camundongos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Complexo Piruvato Desidrogenase/metabolismo , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/genética
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