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BACKGROUND: Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. METHODS: We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4 years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). RESULTS: The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. CONCLUSION: Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes.
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Disfunción Cognitiva , Lisofosfatidilcolinas , Femenino , Humanos , Anciano , Masculino , Estudios Longitudinales , Músculo Esquelético , CogniciónRESUMEN
Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34-70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = - 0.69, p = 0.018, and Cohen's d = - 1.104), anxiety (ρ = - 0.61, p = .046, d = - 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.
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Supervivientes de Cáncer , Neoplasias , Humanos , Fosfocreatina/metabolismo , Salud Mental , Neoplasias/metabolismo , Músculo Esquelético/metabolismo , Estrés OxidativoRESUMEN
INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of many chronic diseases. Whether it is related to cognitive impairment and pathological markers is unknown. METHODS: We examined the associations of in vivo skeletal muscle mitochondrial function (post-exercise recovery rate of phosphocreatine [kPCr] via magnetic resonance [MR] spectroscopy with future mild cognitive impairment (MCI) or dementia, and with positron emission tomography (PET) and blood biomarkers of Alzheimer's disease [AD] and neurodegeneration (i.e., Pittsburgh Compound-B [PiB] distribution volume ratio [DVR] for amyloid beta [Aß], flortaucipir (FTP) standardized uptake value ratio [SUVR] for tau, Aß42 /40 ratio, phosphorylated tau 181 [p-tau181], neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]). RESULTS: After covariate adjustment, each standard deviation (SD) higher kPCr level was associated with 52% lower hazards of developing MCI/dementia, and with 59% lower odds of being PiB positive with specific associations in DVR of frontal, parietal, and temporal regions, and cingulate cortex and pallidum. Higher kPCr level was also associated with lower plasma GFAP. DISCUSSION: In aging, mitochondrial dysfunction may play a vital role in AD pathological changes and neuroinflammation. Highlights Higher in vivo mitochondrial function is related to lower risk of mild cognitive impairment (MCI)/dementia. Higher in vivo mitochondrial function is related to lower amyloid tracer uptake. Higher in vivo mitochondrial function is related to lower plasma neuroinflammation. Mitochondrial dysfunction may play a key role in Alzheimer's disease (AD) and neurodegeneration.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Enfermedades Neuroinflamatorias , Disfunción Cognitiva/metabolismo , Proteínas tau/metabolismo , Biomarcadores , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Tomografía de Emisión de Positrones/métodosRESUMEN
Diffusion-tensor magnetic resonance imaging (DT-MRI) offers objective measures of muscle characteristics, providing insights into age-related changes. We used DT-MRI to probe skeletal muscle microstructure and architecture in a large healthy-aging cohort, with the aim of characterizing age-related differences and comparing these to muscle strength. We recruited 94 participants (43 female; median age = 56, range = 22-89 years) and measured microstructure parameters-fractional anisotropy (FA) and mean diffusivity (MD)-in 12 thigh muscles, and architecture parameters-pennation angle, fascicle length, fiber curvature, and physiological cross-sectional area (PCSA)-in the rectus femoris (RF) and biceps femoris longus (BFL). Knee extension and flexion torques were also measured for comparison to architecture measures. FA and MD were associated with age (ß = 0.33, p = 0.001, R2 = 0.10; and ß = -0.36, p < 0.001, R2 = 0.12), and FA was negatively associated with Type I fiber proportions from the literature (ß = -0.70, p = 0.024, and R2 = 0.43). Pennation angle, fiber curvature, fascicle length, and PCSA were associated with age in the RF (ß = -0.22, 0.26, -0.23, and -0.31, respectively; p < 0.05), while in the BFL only curvature and fascicle length were associated with age (ß = 0.36, and -0.40, respectively; p < 0.001). In the RF, pennation angle and PCSA were associated with strength (ß = 0.29, and 0.46, respectively; p < 0.01); in the BFL, only PCSA was associated with strength (ß = 0.43; p < 0.001). Our results show skeletal muscle architectural changes with aging and intermuscular differences in the microstructure. DT-MRI may prove useful for elucidating muscle changes in the early stages of sarcopenia and monitoring interventions aimed at preventing age-associated microstructural changes in muscle that lead to functional impairment.
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Imagen por Resonancia Magnética , Músculo Esquelético , Humanos , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Imagen por Resonancia Magnética/métodos , Músculo Esquelético/patología , Imagen de Difusión Tensora/métodos , Fuerza Muscular , MetilcelulosaRESUMEN
Analysis of multiexponential decay has remained a topic of active research for over 200 years. This attests to the widespread importance of this problem and to the profound difficulties in characterizing the underlying monoexponential decays. Here, we demonstrate the fundamental improvement in stability and conditioning of this classic problem through extension to a second dimension; we present statistical analysis, Monte-Carlo simulations, and experimental magnetic resonance relaxometry data to support this remarkable fact. Our results are readily generalizable to higher dimensions and provide a potential means of circumventing conventional limits on multiexponential parameter estimation.
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Imagen por Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Método de MontecarloRESUMEN
Background Lower ankle-brachial index (ABI) values within the 0.90 to 1.40 range are associated with poorer mitochondrial oxidative capacity of thigh muscles in cross-sectional analyses. Whether ABI decline is associated with greater declines in thigh muscle oxidative capacity with aging is unknown. Method and Results We analyzed data from 228 participants (100 men) of the BLSA (Baltimore Longitudinal Study of Aging), aged 39 to 97 years, with an ABI between 0.9 and 1.40 at baseline and at follow-up (mean follow-up period of 2.8 years). We examined mitochondrial oxidative capacity of the left thigh muscle, by measuring the postexercise phosphocreatine recovery rate constant (kPCr) from phosphorus-31 magnetic resonance spectroscopy. Greater kPCr indicated higher mitochondrial oxidative capacity. Although kPCr was available on the left leg only, ABI was measured in both legs. Longitudinal rates of change (Change) of left and right ABI and kPCr of the left thigh muscle were estimated using linear mixed effects models, and their association was analyzed by standardized multiple linear regressions. In multivariate analysis including sex, age, baseline kPCr, both left and right baseline ABI, and ABI change in both legs, (kPCr)Change was directly associated with ipsilateral (left) (ABI)Change (standardized [STD]-ß=0.14; P=0.0168) but not with contralateral (right) (ABI)Change (P=0.22). Adjusting for traditional cardiovascular risk factors, this association remained significant (STD-ß=0.18; P=0.0051). (kPCr)Change was steeper in White race participants (STD-ß=0.16; P=0.0122) and body mass index (STD-ß=0.13; P=0.0479). There was no significant association with current smoking status (P=0.63), fasting glucose (P=0.28), heart rate (P=0.67), mean blood pressure (P=0.78), and low-density lipoprotein (P=0.75), high-density lipoprotein (P=0.82), or triglycerides (P=0.15). Conclusions In people without peripheral arterial disease, greater decline in ABI over time, but not baseline ABI, was associated with faster decline in thigh mitochondrial oxidative capacity in the ipsilateral leg. Further studies are needed to examine whether early interventions that improve lower extremity muscle perfusion can improve and prevent the decline of muscle energetics.
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Enfermedad Arterial Periférica , Enfermedades de Transmisión Sexual , Adulto , Anciano , Anciano de 80 o más Años , Índice Tobillo Braquial , Estudios Transversales , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico , Factores de RiesgoRESUMEN
ATP synthase (F1Fo) synthesizes daily our body's weight in ATP, whose production-rate can be transiently increased several-fold to meet changes in energy utilization. Using purified mammalian F1Fo-reconstituted proteoliposomes and isolated mitochondria, we show F1Fo can utilize both ΔΨm-driven H+- and K+-transport to synthesize ATP under physiological pH = 7.2 and K+ = 140 mEq/L conditions. Purely K+-driven ATP synthesis from single F1Fo molecules measured by bioluminescence photon detection could be directly demonstrated along with simultaneous measurements of unitary K+ currents by voltage clamp, both blocked by specific Fo inhibitors. In the presence of K+, compared to osmotically-matched conditions in which this cation is absent, isolated mitochondria display 3.5-fold higher rates of ATP synthesis, at the expense of 2.6-fold higher rates of oxygen consumption, these fluxes being driven by a 2.7:1 K+: H+ stoichiometry. The excellent agreement between the functional data obtained from purified F1Fo single molecule experiments and ATP synthase studied in the intact mitochondrion under unaltered OxPhos coupling by K+ presence, is entirely consistent with K+ transport through the ATP synthase driving the observed increase in ATP synthesis. Thus, both K+ (harnessing ΔΨm) and H+ (harnessing its chemical potential energy, ΔµH) drive ATP generation during normal physiology.
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Adenosina Trifosfato , ATPasas de Translocación de Protón Mitocondriales , Animales , ATPasas de Translocación de Protón Mitocondriales/química , Adenosina Trifosfato/metabolismo , Mitocondrias/metabolismo , Consumo de Oxígeno , Mamíferos/metabolismoRESUMEN
We demonstrated that ATP synthase serves the functions of a primary mitochondrial K+ "uniporter," i.e., the primary way for K+ to enter mitochondria. This K+ entry is proportional to ATP synthesis, regulating matrix volume and energy supply-vs-demand matching. We show that ATP synthase can be upregulated by endogenous survival-related proteins via IF1. We identified a conserved BH3-like domain of IF1 which overlaps its "minimal inhibitory domain" that binds to the ß-subunit of F1. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF1 and exert effects, requiring this interaction, comparable to diazoxide to augment ATP synthase's H+ and K+ flux and ATP synthesis. Bcl-xL and Mcl-1, but not Bcl-2, serve as endogenous regulatory ligands of ATP synthase via interaction with IF1 at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial KATP-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF1-progenitors, we found that IF1 is likely an ancient (â¼2 Gya) Bcl-family member that evolved from primordial bacteria resident in eukaryotes, corresponding to their putative emergence as symbiotic mitochondria, and functioning to prevent their parasitic ATP consumption inside the host cell.
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Mitocondrias , ATPasas de Translocación de Protón Mitocondriales , Teorema de Bayes , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Filogenia , ATPasas de Translocación de Protón Mitocondriales/genética , Mitocondrias/metabolismo , Adenosina Trifosfato/metabolismoRESUMEN
BACKGROUND: Muscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown. METHODS: We examined 380 cognitively normal participants aged 60 and older (53%women, 22%Black) who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr ). Mobility was measured by four walking tests. Associations of baseline kPCr with mobility changes were examined using linear mixed-effects models, adjusted for covariates. In a subset, we examined whether changes in muscle strength and mass affected these associations by adjusting for longitudinal muscle strength, lean mass, and fat mass. RESULTS: Lower baseline kPCr was associated with greater decline in all four mobility measures (ß, p-value: (0.036, 0.020) 6-m usual gait speed; (0.029, 0.038) 2.5-min usual gait speed; (0.034, 0.011) 6-m rapid gait speed; (-0.042, <0.001) 400-m time). In the subset, further adjustment for longitudinal muscle strength, lean mass, and fat mass attenuated longitudinal associations with changes in mobility (Δß reduced 26-63%). CONCLUSION: Among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance.
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Envejecimiento , Mitocondrias , Anciano , Envejecimiento/patología , Baltimore , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Mitocondrias/patología , Músculo Esquelético/metabolismoRESUMEN
The association between blood-based estimates of mitochondrial DNA parameters, mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy load, with skeletal muscle bioenergetic capacity was evaluated in 230 participants of the Baltimore Longitudinal Study of Aging (mean age:74.7 years, 53% women). Participants in the study sample had concurrent data on muscle oxidative capacity (τPCr ) assessed by 31 P magnetic resonance spectroscopy, and mitochondrial DNA parameters estimated from whole-genome sequencing data. In multivariable linear regression models, adjusted for age, sex, extent of phosphocreatine (PCr) depletion, autosomal sequencing coverage, white blood cell total, and differential count, as well as platelet count, mtDNA-CN and heteroplasmy load were not significantly associated with τPCr (both p > 0.05). However, in models evaluating whether the association between mtDNA-CN and τPCr varied by heteroplasmy load, there was a significant interaction between mtDNA-CN and heteroplasmy load (p = 0.037). In stratified analysis, higher mtDNA-CN was significantly associated with lower τPCr among participants with high heteroplasmy load (n = 84, ß (SE) = -0.236 (0.115), p-value = 0.044), but not in those with low heteroplasmy load (n = 146, ß (SE) = 0.046 (0.119), p-value = 0.702). Taken together, mtDNA-CN and heteroplasmy load provide information on muscle bioenergetics. Thus, mitochondrial DNA parameters may be considered proxy measures of mitochondrial function that can be used in large epidemiological studies, especially when comparing subgroups.
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Envejecimiento/genética , Envejecimiento/metabolismo , Variaciones en el Número de Copia de ADN , ADN Mitocondrial/genética , Heteroplasmia , Espectroscopía de Resonancia Magnética/métodos , Mitocondrias/genética , Músculo Esquelético/metabolismo , Estrés Oxidativo/genética , Anciano , Anciano de 80 o más Años , Baltimore , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , FósforoRESUMEN
Skeletal muscle density, as determined by computed tomography (CT), has been shown to decline with age, resulting in increased frailty and morbidity. However, the mechanism underlying this decrease in muscle density remains elusive. We sought to investigate the role of intramyocellular lipid (IMCL) accumulation in the age-related decline in muscle density. Muscle density was measured using computerized tomography (CT), and IMCL content was quantified using in vivo proton magnetic resonance spectroscopy (1H-MRS). The study population consisted of 314 healthy participants (142 men, 32-98 years) of the Baltimore Longitudinal Study of Aging (BLSA). In addition to IMCL quantification, obesity-related covariates were measured, including body mass index (BMI), waist circumference, and circulating triglyceride concentration. Higher IMCL concentrations were significantly correlated with lower muscle density in older individuals, independent of age, sex, race, and the obesity-associated covariates (p < 0.01). Lower muscle density was also significantly associated with greater age-adjusted IMCL, a variable we constructed using LOESS regression (p < 0.05). Our results suggest that the accumulation of IMCL may be associated with a decrease in muscle density. This may serve to define a potential therapeutic target for treatment of age-associated decreased muscle function.
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BACKGROUND: Central arterial stiffness (CAS) is associated with elevated arterial blood pressure (BP) and is likely associated with stiffening of cerebral artery walls, with attendant cerebral hypoperfusion, neuronal density loss and cognitive decline. Dahl salt-sensitive (Dahl-S) rats exhibit age-associated hypertension and memory loss, even on a normal salt intake. METHOD: We sought to explore whether central arterial pulse wave velocity (PWV), a marker of CAS, is associated with hippocampal cerebral blood flow (CBF) and neuronal density in hypertensive Dahl-S rats. We measured systolic BP (by tail-cuff plethysmography), aortic PWV (by echocardiography) and CBF and N-acetyl aspartate (NAA) (by magnetic resonance imaging) in 6 month-old male Dahl-S rats (nâ=â12). RESULTS: Greater PWV was significantly associated with lower CBF and lower NAA concentration in the hippocampus, supporting a role of CAS in cerebrovascular dysfunction and decline in cognitive performance with aging. CONCLUSION: These findings implicate increased CAS in cerebral hypoperfusion and loss of neuronal density and function in the Dahl-S model of age-associated cardiovascular dysfunction.
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Hipertensión , Rigidez Vascular , Animales , Ácido Aspártico/análogos & derivados , Presión Sanguínea , Hipocampo , Masculino , Análisis de la Onda del Pulso , Ratas , Ratas Endogámicas DahlRESUMEN
Aging is associated with distinct phenotypical, physiological, and functional changes, leading to disease and death. The progression of aging-related traits varies widely among individuals, influenced by their environment, lifestyle, and genetics. In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and toward redox-related pathways, mainly in liver and heart. Collectively, the data provide a framework to further understand and characterize processes of aging at the individual organism and organ levels.
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Envejecimiento/metabolismo , Metabolismo Energético , Fragilidad , Metaboloma , Factores de Edad , Animales , Biomarcadores/sangre , Composición Corporal , Remodelación Ósea , Fragilidad/diagnóstico por imagen , Fragilidad/metabolismo , Fragilidad/fisiopatología , Estado Funcional , Fuerza de la Mano , Resistencia a la Insulina , Hígado/metabolismo , Longevidad , Masculino , Metabolómica , Ratones Endogámicos C57BL , Miocardio/metabolismo , Fenotipo , Factores Sexuales , Velocidad al CaminarRESUMEN
Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.
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Drogas de Diseño/uso terapéutico , Nervio Hipogloso/efectos de los fármacos , Músculos Faríngeos/efectos de los fármacos , Receptores de Droga/efectos de los fármacos , Respiración/efectos de los fármacos , Apnea Obstructiva del Sueño/tratamiento farmacológico , Apnea Obstructiva del Sueño/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , RatonesRESUMEN
BACKGROUND: Although mitochondrial dysfunction appears to be a contributing factor in the pathogenesis of cardiovascular and metabolic diseases, empirical data on this association are still lacking. This study evaluated whether mitochondrial oxidative capacity, as assessed by phosphorus magnetic resonance spectroscopy, was associated with cardiovascular risk, as estimated by the Framingham Risk Score (FRS), and with a clinical history of cardiovascular disease (CVD), in community-dwelling adults. METHOD: A total of 616 subjects from the Baltimore Longitudinal Study of Aging (mean age 66 years) underwent a comprehensive clinical evaluation. Mitochondrial oxidative capacity in skeletal muscle was assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy. Multivariate regression models were employed to determine the cross-sectional association of mitochondrial oxidative capacity with FRS and history of CVD. RESULTS: Decreased mitochondrial oxidative capacity was strongly associated with higher FRS independent of age, body composition, and physical activity. Lower oxidative capacity was also associated with a history of positive of CVD and higher number of CVD events. CONCLUSIONS: We speculate that the observed association could reflect the effect of an excessive production of oxidative species by dysfunctional mitochondria. Furthermore, decreased energy production could hamper the functionality of heart and vessels. In turn, a malfunctioning cardiovascular apparatus could fail to deliver the oxygen necessary for optimal mitochondrial energy production, therefore creating a vicious cycle. Longitudinal studies are necessary to ascertain the directionality of the association and the eventual presence of common pathogenetic roots. In conclusion, mitochondria could represent an important target for intervention in cardiovascular health.
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Envejecimiento/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Mitocondrias Musculares/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Baltimore , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fosforilación Oxidativa , Estrés Oxidativo , Factores de RiesgoRESUMEN
Although a persistent inflammatory state has long been associated with aging and negative health outcomes, the underlying mechanisms remain unclear. Mitochondrial dysfunction has been proposed as a cause of inflammaging, but evidence of an association in humans is lacking. In this study, we analyzed the cross-sectional association between inflammatory biomarkers and mitochondrial oxidative capacity in skeletal muscle, assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy, in a population of 669 adults (mean age 67 years) from the Baltimore Longitudinal Study of Aging. We observed that participants with lower mitochondrial oxidative capacity exhibited hallmarks of inflammation, specifically markedly higher levels of interleukin-6 and C-reactive protein, as well as increased erythrocyte sedimentation rate when compared with participants with better oxidative capacity, independent of age and sex. We speculate that this association reflects the observation that products of damaged mitochondria, such as mitochondrial DNA, activate multiple pathways that lead to inflammation. Furthermore, excess production of oxidative species (ROS) by dysfunctional mitochondria could trigger inflammation either directly via NF-κB or through oxidative damage to proteins, lipids, and nucleic acids. Longitudinal studies are necessary to ascertain whether and through which mechanisms mitochondrial dysfunction activate inflammation or whether both these phenomena derive from a common root.
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Envejecimiento , Mitocondrias , Anciano , Baltimore , Estudios Transversales , Humanos , Inflamación , Estudios LongitudinalesRESUMEN
Topoisomerase 3ß (Top3ß) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3ß mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3ß knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3ß is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3ß deletion causes cognitive impairment and psychiatric disorders.
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Disfunción Cognitiva/genética , ADN-Topoisomerasas de Tipo I/genética , Trastornos Mentales/genética , Neurogénesis/genética , Plasticidad Neuronal/genética , Animales , Técnicas de Observación Conductual , Conducta Animal , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Femenino , Hipocampo/citología , Hipocampo/diagnóstico por imagen , Hipocampo/crecimiento & desarrollo , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/patología , Ratones , Ratones Noqueados , Neuronas/patología , Técnicas Estereotáxicas , Potenciales Sinápticos/genética , Transcripción Genética/fisiologíaRESUMEN
Resting metabolic rate (RMR) tends to decline with aging. The age-trajectory of decline in RMR is similar to changes that occur in muscle mass, muscle strength, and fitness, but while the decline in these phenotypes has been related to changes of mitochondrial function and oxidative capacity, whether lower RMR is associated with poorer mitochondrial oxidative capacity is unknown. In 619 participants of the Baltimore Longitudinal Study of Aging, we analyzed the cross-sectional association between RMR (kcal/day), assessed by indirect calorimetry, and skeletal muscle maximal oxidative phosphorylation capacity, assessed as postexercise phosphocreatine recovery time constant (τâPCr), by phosphorous magnetic resonance spectroscopy. Linear regression models were used to evaluate the relationship between τâPCr and RMR, adjusting for potential confounders. Independent of age, sex, lean body mass, muscle density, and fat mass, higher RMR was significantly associated with shorter τâPCr, indicating greater mitochondrial oxidative capacity. Higher RMR is associated with a higher mitochondrial oxidative capacity in skeletal muscle. This association may reflect a relationship between better muscle quality and greater mitochondrial health.
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Envejecimiento/metabolismo , Metabolismo Basal/fisiología , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxígeno/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Baltimore , Composición Corporal , Calorimetría Indirecta , Enfermedad Crónica/epidemiología , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Adequate support of energy for biological activities and during fluctuation of energetic demand is crucial for healthy aging; however, mechanisms for energy decline as well as compensatory mechanisms that counteract such decline remain unclear. We conducted a discovery proteomic study of skeletal muscle in 57 healthy adults (22 women and 35 men; aged 23-87 years) to identify proteins overrepresented and underrepresented with better muscle oxidative capacity, a robust measure of in vivo mitochondrial function, independent of age, sex, and physical activity. Muscle oxidative capacity was assessed by 31 P magnetic resonance spectroscopy postexercise phosphocreatine (PCr) recovery time (τPCr ) in the vastus lateralis muscle, with smaller τPCr values reflecting better oxidative capacity. Of the 4,300 proteins quantified by LC-MS in muscle biopsies, 253 were significantly overrepresented with better muscle oxidative capacity. Enrichment analysis revealed three major protein clusters: (a) proteins involved in key energetic mitochondrial functions especially complex I of the electron transport chain, tricarboxylic acid (TCA) cycle, fatty acid oxidation, and mitochondrial ABC transporters; (b) spliceosome proteins that regulate mRNA alternative splicing machinery, and (c) proteins involved in translation within mitochondria. Our findings suggest that alternative splicing and mechanisms that modulate mitochondrial protein synthesis are central features of the molecular mechanisms aimed at maintaining mitochondrial function in the face of impairment. Whether these mechanisms are compensatory attempt to counteract the effect of aging on mitochondrial function should be further tested in longitudinal studies.
Asunto(s)
Envejecimiento , Músculo Esquelético/metabolismo , Proteómica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Oxidación-Reducción , Fosfatos , Adulto JovenRESUMEN
Total serum magnesium is a common clinical measurement for assessing magnesium status; however, magnesium in blood represents less than 1% of the body's total magnesium content. We measured intramuscular ionized magnesium by phosphorus magnetic resonance spectroscopy (31P-MRS) and tested the hypothesis that this measure better correlates with skeletal muscle function and captures more closely the effect of aging than the traditional measure of total serum magnesium. Data were collected from 441 participants (age 24-98 years) in the Baltimore Longitudinal Study of Aging (BLSA), a study of normative aging that encompasses a broad age range. Results showed that intramuscular ionized magnesium was negatively associated with age (ß = -0.29, p < 0.001, R 2 = 0.08) and positively associated with knee-extension strength (ß = 0.31, p < 0.001, and R 2 = 0.1 in women; and ß = 0.2, p = 0.003, and R 2 = 0.04 in men), while total serum magnesium showed no association with age or strength (p = 0.27 and 0.1, respectively). Intramuscular ionized magnesium was significantly lower in women that in men (p < 0.001), perhaps due to chronic latent Mg deficiency in women that is not otherwise detected by serum magnesium levels. Based on these findings, we suggest that intramuscular ionized magnesium from 31P-MRS is a better clinical measure of magnesium status than total serum magnesium, and could be measured when muscle weakness of unidentified etiology is detected. It may also be used to monitor the effectiveness of oral magnesium interventions, including supplementation.