RESUMO
Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed. Here we show that the autophagy regulator TP53INP2/TRP53INP2 is decreased during aging in mouse and human skeletal muscle. Importantly, chronic activation of autophagy by muscle-specific overexpression of TRP53INP2 prevents sarcopenia and the decline of muscle function in mice. Acute re-expression of TRP53INP2 in aged mice also improves muscle atrophy, enhances mitophagy, and reduces ROS production. In humans, high levels of TP53INP2 in muscle are associated with increased muscle strength and healthy aging. Our findings highlight the relevance of an active muscle autophagy in the maintenance of muscle mass and prevention of sarcopenia.Abbreviation: ATG7: autophagy related 7; BMI: body mass index; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ROS: reactive oxygen species; TP53INP2: tumor protein p53 inducible nuclear protein 2; WT: wild type.
Assuntos
Autofagia , Músculo Esquelético , Sarcopenia , Animais , Humanos , Masculino , Camundongos , Autofagia/fisiologia , Envelhecimento Saudável/fisiologia , Envelhecimento Saudável/metabolismo , Camundongos Endogâmicos C57BL , Mitofagia/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas Nucleares , Espécies Reativas de Oxigênio/metabolismo , Sarcopenia/patologia , Sarcopenia/metabolismoRESUMO
In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.
Assuntos
Cálcio , Retículo Endoplasmático , GTP Fosfo-Hidrolases , Mitocôndrias , Proteínas Mitocondriais , Animais , Camundongos , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Fígado/metabolismo , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Isoformas de Proteínas , Camundongos Knockout , Humanos , Camundongos Endogâmicos C57BL , Células HeLa , Processamento Alternativo , Estresse do Retículo EndoplasmáticoRESUMO
Background: Takayasu's disease (TM) is a vasculitis of the aorta and its main branches, Infectious diseases, especially Mycobacterium tuberculosis, can be a trigger for the development of TM by a hypersensitivity reaction, but paradoxically very few cases of the disease are reported in the literature review. Materials and methods: Through a retrospective study carried out in the departments of internal medicine and cardiology of the Centre hospitalier universitaire de Libreville (CHUL) in Gabon, we identified all the observations of TM diagnosed in the said departments from 03/2014 to 05/2022, and rediscussed them on the basis of the criteria of Sharma et al. of 1996. Results: Five patients (3 men, 2 women), with an average age of 38.4 years were found. 2/5 patients reported a history of pulmonary tuberculosis. There was a change in general condition (n=4), fever (n=2), arterial hypertension (n=4), a decrease in the radial pulse (n=2), rheumatological manifestations (n=3), involvement of the serous membranes (n=3). CRP was positive (n=4), and HIV1,2 serology negative (n=5). Echocardiography found pulmonary arterial hypertension (n=1), constrictive pericarditis (n=1) and valvular involvement (minimal aortic insufficiency) (n=1), and typing of aortic involvement by computed tomography or CT angiography staged Takayasu's disease as type IIa (n=2), IIb (n=2) and IV (n=1). The patients were treated with oral corticosteroid therapy (n=5) combined with methotrexate (n=4) and azathioprine (n=1). Discussion: The criteria of Sharma et al. from 1996, suggest a high probability of TM with a sensitivity of 92.5% and a specificity of 95%. In sub-Saharan Africa, TM requires the elimination of certain differential diagnoses, particularly syphillis, tuberculosis, salmonellosis, and atherosclerosis. Corticosteroid therapy (coupled with immunosuppressive treatment) remains effective, allowing significant remission of the disease, but comes up against the risk of opportunistic infections. Conclusion: There is a contrast between the involvement of Mycobacterium tuberculosis in the etiopathogenesis of TM on the one hand and the endemic nature of tuberculosis on the African continent on the other hand; which contrasts with the few cases reported in sub-Saharan Africa.
Assuntos
Mycobacterium tuberculosis , Arterite de Takayasu , Masculino , Humanos , Feminino , Adulto , Estudos Retrospectivos , Azatioprina , Metotrexato , Arterite de Takayasu/diagnóstico , África Subsaariana/epidemiologia , CorticosteroidesRESUMO
Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.
Assuntos
Sarcopenia , Envelhecimento , Animais , Homeostase , Humanos , Inflamação/metabolismo , Lisossomos/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Atrofia Muscular/metabolismo , Sarcopenia/metabolismoRESUMO
Purpose: Psychiatric patients present an elevated rate of smoking, and the smoking habit is related to a high morbidity and mortality in this collective. The aim of this study was to determine the prevalence of smoking in patients admitted for psychiatric disorders and its relationship with respiratory disease, the prevalence of COPD, and alterations in the quality of life. Patients and methods: A cross-sectional, observational study was conducted and detailed information on smoking and respiratory symptomatology was obtained. The study participants underwent the following tests: spirometry with bronchodilator test, Fagerström test, determination of physical activity using the LCADL questionnaire, and evaluation of quality of life with the EuroQoL-5 Dimensions EQ-5D questionnaire. Results: Two hundred seventy-six patients (mean age 56.8 years) were included: 155 with schizophrenia (87.7% smokers), 46 with depressive or anxiety disorders (54.3% smokers), and 49 and 25 with intellectual disability and dementia (43.2% smokers), respectively. The mean Fagerström test score was 5.75 points. Smokers presented with cough (47.6%), expectoration (41.4%), and chronic bronchitis (36.6%). The prevalence of COPD in the total population was 28.9%. The EQ-5D and LCADL scores were better in smokers because of their younger age and lesser psychiatric involvement. A high prevalence of smoking was observed in the psychiatric population studied, and 28.9% were diagnosed with COPD. Conclusion: Smokers presented many more respiratory symptoms and chronic bronchitis but did not present a worse quality of life or physical activity due to their younger age and milder psychiatric involvement.
Assuntos
Hospitais Psiquiátricos/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologia , Adulto , Idoso , Transtornos de Ansiedade/epidemiologia , Estudos Transversais , Demência/epidemiologia , Transtorno Depressivo/epidemiologia , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Qualidade de Vida , Fatores de Risco , Esquizofrenia/epidemiologia , Espanha/epidemiologia , Espirometria , Inquéritos e Questionários , Avaliação de SintomasRESUMO
BACKGROUND: A recent approach for the management of chronic obstructive pulmonary disease (COPD) is the measurement of systemic biomarkers. The aim of this study was to evaluate the usefulness of mid regional pro-atrial natriuretic peptide (MR-proANP) to predict short and long term prognosis. METHODS: We included 318 COPD patients: 46 in a stable phase, 217 undergoing an exacerbation and 55 with pneumonia. Serum samples were collected at admission. For 20 exacerbated patients, we also collected a second sample one month later. MR-proANP was measured by an inmunofluorescent assay. RESULTS: Statistically higher levels of MR-proANP were found in patients with pneumonia when comparing to patients in the stable state (p=0.031). For those patients with paired samples, MR-proANP decreased statistically one month later (p=0.027). MR-proANP showed significant lower levels in exacerbations with isolation of pathogenic bacteria (p=0.011). MR-proANP levels were higher in patients that died within one month, decreasing as long as the moment of death occurred later on (p=0.163). CONCLUSIONS: The identification of exacerbation etiology by means of MR-proANP is not clinically reliable. Levels of MR-proANP vary depending on the clinical status, being higher during pneumonia in comparison to the stable state. MR-proANP levels were higher in patients that died within one month after the exacerbation episode.
Assuntos
Fator Natriurético Atrial/análise , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Idoso , Fator Natriurético Atrial/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pneumonia/diagnóstico , Pneumonia/etiologia , Prognóstico , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologiaRESUMO
OBJECTIVE: The identification of biological markers in order to assess different aspects of COPD is an area of growing interest. The objective of this study was to investigate whether levels of procalcitonin (PCT), C-reactive protein (CRP), and neopterin in COPD patients could be useful in identifying the etiological origin of the exacerbation and assessing its prognosis. METHODS: We included 318 consecutive COPD patients: 46 in a stable phase, 217 undergoing an exacerbation, and 55 with pneumonia. A serum sample was collected from each patient at the time of being included in the study. A second sample was also collected 1 month later from 23 patients in the exacerbation group. We compared the characteristics, biomarker levels, microbiological findings, and prognosis in each patient group. PCT and CRP were measured using an immunofluorescence assay. Neopterin levels were measured using a competitive immunoassay. RESULTS: PCT and CRP showed significant differences among the three patient groups, being higher in patients with pneumonia, followed by patients with exacerbation (P < 0.0001). For the 23 patients with paired samples, PCT and CRP levels decreased 1 month after the exacerbation episode, while neopterin increased. Neopterin showed significantly lower levels in exacerbations with isolation of pathogenic bacteria, but no differences were found for PCT and CRP. No significant differences were found when comparing biomarker levels according to the Gram result: PCT (P = 0.191), CRP (P = 0.080), and neopterin (P = 0.109). However, median values of PCT and CRP were high for Streptococcus pneumoniae, Staphylococcus aureus, and enterobacteria. All biomarkers were higher in patients who died within 1 month after the sample collection than in patients who died later on. CONCLUSIONS: According to our results, biomarker levels vary depending on the clinical status. However, the identification of the etiology of infectious exacerbation by means of circulating biomarkers is encouraging, but its main disadvantage is the absence of a microbiological gold standard, to definitively demonstrate their value. High biomarker levels during an exacerbation episode correlate with the short-term prognosis, and therefore their measurement can be useful for COPD management.
Assuntos
Proteína C-Reativa/metabolismo , Calcitonina/sangue , Mediadores da Inflamação/sangue , Neopterina/sangue , Precursores de Proteínas/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Imunofluorescência , Volume Expiratório Forçado , Humanos , Imunoensaio , Estimativa de Kaplan-Meier , Pulmão/microbiologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Espanha , Escarro/microbiologia , Fatores de TempoRESUMO
The aim of this study was to evaluate the utility of pneumococcal urinary antigen detection (Binax Now Streptococcus pneumoniae Antigen Test) in diagnosing pneumococcal exacerbation of chronic obstructive pulmonary disease (COPD). Forty-six patients with S. pneumoniae isolation in sputum culture were studied (29 collected in stable period and 17 collected during exacerbation). In the 29 patients with samples collected in a stable period the antigen was detected in 3 cases (10.3%) using nonconcentrated urine (NCU), and in 12 cases (41.4%) using concentrated urine (CU). Regarding patients recruited during an exacerbation period, the antigen was detected in 3 cases (17.6%) using NCU, and in 13 cases (76.5%) when CU was used. For the evaluation of the specificity of the ICT test we also tested 72 cases in which pneumococcus was not isolated in the sputum sample. ICT was positive in 1NCU and 9CU of these patients. To have had at least one previous exacerbation (P=0.024), at least one exacerbation that required hospitalization (P=0.027), and a pneumonia episode in the year before (P=0.010) had statistically significant associated with the detection of specific antigen in CU. Using NCU, the only significant association was found when a previous pneumonia in the year before had occurred (P=0.006). In summary, a positive result of pneumococcal urinary antigen from a COPD patient, in both bronchial exacerbation and pneumonia, should be evaluated with caution because the antigen detected could be related with previous infectious episode.