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1.
Circ Res ; 124(1): 121-141, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605420

RESUMO

Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction). Cardiovascular outcomes, hospitalization, and prognosis are worse for patients with diabetes mellitus relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes mellitus the high prevalence of HF persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. This review summarizes the state of knowledge about the impact of existing antihyperglycemic therapies on HF and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for HF and review evidence that addresses their efficacy in the context of diabetes mellitus. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity, and altered signal transduction such as GRK (g-protein receptor kinase) signaling, renin angiotensin aldosterone signaling and ß-2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of HF in the context of type 2 diabetes mellitus. Successful targeting of these pathways could alter the prognosis and risk of HF beyond what is currently achieved using existing antihyperglycemic and HF therapeutics.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/fisiopatologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipoglicemiantes/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Medição de Risco , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Função Ventricular/efeitos dos fármacos
2.
J Proteome Res ; 19(8): 3438-3451, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32609523

RESUMO

Muscle atrophy is a deleterious consequence of physical inactivity and is associated with increased morbidity and mortality. The aim of this study was to decipher the mechanisms involved in disuse muscle atrophy in eight healthy men using a 21 day bed rest with a cross-over design (control, with resistive vibration exercise (RVE), or RVE combined with whey protein supplementation and an alkaline salt (NEX)). The main physiological findings show a significant reduction in whole-body fat-free mass (CON -4.1%, RVE -4.3%, NEX -2.7%, p < 0.05), maximal oxygen consumption (CON -20.5%, RVE -6.46%, NEX -7.9%, p < 0.05), and maximal voluntary contraction (CON -15%, RVE -12%, and NEX -9.5%, p < 0.05) and a reduction in mitochondrial enzyme activity (CON -30.7%, RVE -31.3%, NEX -17%, p < 0.05). The benefits of nutrition and exercise countermeasure were evident with an increase in leg lean mass (CON -1.7%, RVE +8.9%, NEX +15%, p < 0.05). Changes to the vastus lateralis muscle proteome were characterized using mass spectrometry-based label-free quantitative proteomics, the findings of which suggest alterations to cell metabolism, mitochondrial metabolism, protein synthesis, and degradation pathways during bed rest. The observed changes were partially mitigated during RVE, but there were no significant pathway changes during the NEX trial. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD006882. In conclusion, resistive vibration exercise, when combined with whey/alkalizing salt supplementation, could be an effective strategy to prevent skeletal muscle protein changes, muscle atrophy, and insulin sensitivity during medium duration bed rest.


Assuntos
Repouso em Cama , Vibração , Repouso em Cama/efeitos adversos , Estudos Cross-Over , Suplementos Nutricionais , Humanos , Masculino , Músculo Esquelético , Proteoma , Soro do Leite , Proteínas do Soro do Leite
3.
Circ Res ; 122(1): 58-73, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29092894

RESUMO

RATIONALE: Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. OBJECTIVE: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. METHODS AND RESULTS: Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. CONCLUSIONS: Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Dinaminas/metabolismo , Dinâmica Mitocondrial/fisiologia , Miócitos Cardíacos/metabolismo , Atrofia Óptica Autossômica Dominante/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Preparação de Coração Isolado/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Ratos , Ratos Wistar
4.
Diabetologia ; 60(8): 1491-1501, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28500394

RESUMO

AIMS/HYPOTHESIS: Physical inactivity has broad implications for human disease including insulin resistance, sarcopenia and obesity. The present study tested the hypothesis that (1) impaired mitochondrial respiration is linked with blunted insulin sensitivity and loss of muscle mass in healthy young men, and (2) resistive vibration exercise (RVE) would mitigate the negative metabolic effects of bed rest. METHODS: Participants (n = 9) were maintained in energy balance during 21 days of bed rest with RVE and without (CON) in a crossover study. Mitochondrial respiration was determined by high-resolution respirometry in permeabilised fibre bundles from biopsies of the vastus lateralis. A hyperinsulinaemic-euglycaemic clamp was used to determine insulin sensitivity, and body composition was assessed by dual-energy x-ray absorptiometry (DEXA). RESULTS: Body mass (-3.2 ± 0.5 kg vs -2.8 ± 0.4 kg for CON and RVE, respectively, p < 0.05), fat-free mass (-2.9 ± 0.5 kg vs -2.7 ± 0.5 kg, p < 0.05) and peak oxygen consumption ([Formula: see text]) (10-15%, p < 0.05) were all reduced following bed rest. Bed rest decreased insulin sensitivity in the CON group (0.04 ± 0.002 mg kgFFM-1 [pmol l-1] min-1 vs 0.03 ± 0.002 mg kgFFM-1 [pmol l-1] min-1 for baseline vs post-CON), while RVE mitigated this response (0.04 ± 0.003 mg kgFFM-1 [pmol l-1] min-1). Mitochondrial respiration (oxidative phosphorylation and electron transport system capacity) decreased in the CON group but not in the RVE group when expressed relative to tissue weight but not when normalised for citrate synthase activity. LEAK respiration, indicating a decrease in mitochondrial uncoupling, was the only component to remain significantly lower in the CON group after normalisation for citrate synthase. This was accompanied by a significant decrease in adenine nucleotide translocase protein content. CONCLUSIONS/INTERPRETATION: Reductions in muscle mitochondrial respiration occur concomitantly with insulin resistance and loss of muscle mass during bed rest and may play a role in the adaptations to physical inactivity. Significantly, we show that RVE is an effective strategy to partially prevent some of the deleterious metabolic effects of bed rest.


Assuntos
Repouso em Cama , Resistência à Insulina/fisiologia , Mitocôndrias/metabolismo , Músculo Esquelético/fisiologia , Absorciometria de Fóton , Adulto , Composição Corporal/fisiologia , Estudos Cross-Over , Metabolismo Energético/fisiologia , Técnica Clamp de Glucose , Humanos , Masculino
5.
Trends Endocrinol Metab ; 33(10): 710-721, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35945104

RESUMO

The mitochondria are double-membrane organelles integral for energy metabolism. Mitochondrial dynamics is regulated by inner and outer mitochondrial membrane (IMM and OMM) proteins, which promote fission and fusion. Optic atrophy 1 (OPA1) regulates IMM fusion, prevents apoptosis, and is a key regulator of morphological change in skeletal and cardiac muscle physiology and pathophysiology. OPA1 fuses the inner membranes of adjacent mitochondria, allowing for an increase in oxidative phosphorylation (OXPHOS). Considering the importance of energy metabolism in whole-body physiology, OPA1 and its regulators have been proposed as novel targets for the treatment of skeletal muscle atrophy and heart failure. Here, we review the role and regulation of OPA1 in skeletal muscle and cardiac pathophysiology, epitomizing its critical role in the cell.


Assuntos
GTP Fosfo-Hidrolases , Dinâmica Mitocondrial , Músculo Esquelético , Miocárdio , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo
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