Reduced uremic metabolites are prominent feature of sarcopenia, distinct from antioxidative markers for frailty.
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ABSTRACT:
SUBMITTER: Kameda M
PROVIDER: S-EPMC8457568 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Reduced uremic metabolites are prominent feature of sarcopenia, distinct from antioxidative markers for frailty.
Kameda Masahiro M Teruya Takayuki T Yanagida Mitsuhiro M Kondoh Hiroshi H
Aging 20210907 17
Due to global aging, frailty and sarcopenia are increasing. Sarcopenia is defined as loss of volume and strength of skeletal muscle in elderlies, while frailty involves multiple domains of aging-related dysfunction, impaired cognition, hypomobility, and decreased social activity. However, little is known about the metabolic basis of sarcopenia, either shared with or discrete from frailty. Here we analyzed comprehensive metabolomic data of human blood in relation to sarcopenia, previously collect ...[more]
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Project description:<p>Due to global aging, frailty and sarcopenia are increasing. Sarcopenia is defined as loss of volume and strength of skeletal muscle in elderlies, while frailty involves multiple domains of aging-related dysfunction, impaired cognition, hypomobility and decreased social activity. However, little is known about the metabolic basis of sarcopenia, either shared with or discrete from frailty. Here we analyzed comprehensive metabolomic data of human blood in relation to sarcopenia, previously collected from 19 elderly participants in our frailty study. Among 131 metabolites, we identified 22 sarcopenia markers, distinct from 15 frailty markers, mainly including antioxidants, although sarcopenia overlaps clinically with physical frailty. Notably, 21 metabolites that decline in sarcopenia or low SMI are uremic compounds that increase in kidney dysfunction. These comprise TCA cycle, urea cycle, nitrogen and methylated metabolites. Sarcopenia markers imply a close link between muscle and kidney function, while frailty markers define a state vulnerable to oxidative stress.</p>
2022-10-19 | MTBLS3341 | MetaboLights
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Project description:BackgroundAlthough low alanine aminotransferase (ALT) levels have been associated with poor outcomes in the elderly population, the determinants subtending this association have been poorly explored. To gain insight into this topic, we analyzed data from a prospective population-based database (InCHIANTI study) in which frailty, disability, sarcopenia, and pyridoxine levels were systematically assessed.MethodsData are from 765 participants aged more than 65 years (mean age 75.3 years, women 61.8%), without chronic liver disease, malignancies, or alcohol abuse. Frailty was defined according to Fried criteria, sarcopenia through peripheral Quantitative-Computed-Tomography (lowest gender-specific tertile of the residuals of a linear regression of muscle mass from height and fat mass), and disability as self-reported need for help in at least one basic daily living activity. Associations of ALT with overall and cardiovascular mortality were assessed by Cox-models with time-dependent covariates.ResultsALT activity was inversely associated with frailty, sarcopenia, disability, and pyridoxine deficiency; however, higher ALT was confirmed to be protective with respect of overall and cardiovascular mortality even in multiple-adjusted models including all these covariates (overall: hazard ratio [HR] 0.98 [0.96-1], p = .02; cardiovascular: 0.94 [0.9-0.98], p < .01). The association between ALT activity and mortality was nonlinear (J-shaped), and subjects in the lower quintiles of ALT levels showed a sharply increased overall and cardiovascular mortality.ConclusionsThese results suggest that reduced ALT levels in older individuals can be considered as a marker of frailty, disability, and sarcopenia, and as an independent predictor of adverse outcomes. The possible relationship between reduced ALT and impaired hepatic metabolic functions should be explored.
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Project description:IntroductionArrhythmogenic cardiomyopathy (ACM) is hereditary cardiomyopathy caused by pathogenic variants (mutations) in genes encoding the intercalated disc (ID), particularly desmosome proteins. ACM caused by mutations in the DSP gene encoding desmoplakin (DSP) is characterized by the prominence of cell death, myocardial fibrosis, and inflammation, and is referred to as desmoplakin cardiomyopathy.AimThe aim of this article was to gain insight into the pathogenesis of DSP cardiomyopathy.Methods and resultsThe Dsp gene was exclusively deleted in cardiac myocytes using tamoxifen-inducible MerCreMer (Myh6-Mcm Tam) and floxed Dsp (Dsp F/F) mice (Myh6-Mcm Tam:Dsp F/F). Recombination was induced upon subcutaneous injection of tamoxifen (30 mg/kg/d) for 5 days starting post-natal day 14. Survival was analyzed by Kaplan-Meier plots, cardiac function by echocardiography, arrhythmias by rhythm monitoring, and gene expression by RNA-Seq, immunoblotting, and immunofluorescence techniques. Cell death was analyzed by the TUNEL assay and the expression levels of specific markers were by RT-PCR and immunoblotting. Myocardial fibrosis was assessed by picrosirius red staining of the myocardial sections, RT-PCR, and immunoblotting. The Myh6-Mcm Tam: Dsp F/F mice showed extensive molecular remodeling of the IDs and the differential expression of ~10,000 genes, which predicted activation of KDM5A, IRFs, and NFκB and suppression of PPARGC1A and RB1, among others in the DSP-deficient myocytes. Gene set enrichment analysis predicted activation of the TNFα/NFκB pathway, inflammation, cell death programs, and fibrosis. Analysis of cell death markers indicated PANoptosis, comprised of apoptosis (increased CASP3, CASP8, BAD and reduced BCL2), necroptosis (increased RIPK1, RIPK3, and MLKL), and pyroptosis (increased GSDMD and ASC or PYCARD) in the DSP-deficient myocytes. Transcript levels of the pro-inflammatory and pro-fibrotic genes were increased and myocardial fibrosis comprised ~25% of the myocardium in the DSP-deficient hearts. The Myh6-Mcm Tam:Dsp F/F mice showed severe cardiac systolic dysfunction and ventricular arrhythmias, and died prematurely with a median survival rate of ~2 months.ConclusionThe findings identify PANoptosis as a prominent phenotypic feature of DSP cardiomyopathy and set the stage for delineating the specific molecular mechanisms involved in its pathogenesis. The model also provides the opportunity to test the effects of pharmacological and genetic interventions on myocardial fibrosis and cell death.
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Project description:In patients with decompensated cirrhosis, sarcopenia and frailty are prevalent. Although several definitions exist for these terms, in the field of hepatology, sarcopenia has commonly been defined as loss of muscle mass, and frailty has been broadly defined as the phenotypic manifestation of the loss of muscle function. Prompt recognition and accurate assessment of these conditions are critical as they are both strongly associated with morbidity, mortality, poor quality of life and worse post-liver transplant outcomes in patients with cirrhosis. In this review, we describe the complex pathophysiology that underlies the clinical phenotypes of sarcopenia and frailty, their association with decompensation, and provide an overview of tools to assess these conditions in patients with cirrhosis. When available, we highlight data focusing on patients with acutely decompensated cirrhosis, such as inpatients, as this is an area of unmet clinical need. Finally, we discuss management strategies to reverse and/or prevent the development of sarcopenia and frailty, which include adequate nutritional intake of calories and protein, as well as regular exercise of at least moderate intensity, with a mix of aerobic and resistance training. Key knowledge gaps in our understanding of sarcopenia and frailty in decompensated cirrhosis remain, including best methods to measure muscle mass and function in the inpatient setting, racial/ethnic variation in the development and presentation of sarcopenia and frailty, and optimal clinical metrics to assess response to therapeutic interventions that translate into a reduction in adverse outcomes associated with these conditions.
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Project description:BackgroundFrailty, characterized by vulnerability, reduced reserves and increased susceptibility to severe events, is a significant concern in chronic haemodialysis (HD) patients. Sarcopenia, corresponding to the progressive loss of muscle mass and strength, may contribute to frailty by reducing functional capacity, mobility and autonomy. However, consensus lacks on the optimal bedside frailty index for chronic HD patients. This study investigated the influence of frailty on chronic HD patient survival and explored the associated factors.MethodsA total of 135 patients were enrolled from January to April 2019 and then followed up prospectively until April 2022. At inclusion, frailty was assessed by the Timed Up and Go (TUG) and Short Physical Performance Battery (SPPB) tests including gait speed, standing balance and lower limb muscle strength.ResultsFrom a total of 114 prevalent chronic HD patients (66% men, age 67.6 ± 15.1 years), 30 died during the follow-up period of 23.7 months (range 16.8-34.3). Deceased patients were older, had more comorbidities and a higher sarcopenia prevalence (P < .05). The TUG and SPPB test scores were significantly reduced in patients who had died [SPPB total score: 7.2 ± 3.3 versus 9.4 ± 2.5; TUG time 8.7 ± 5.8 versus 13.8 ± 10.5 (P < .05)]. Multivariate analysis showed that a higher SPPB score (total value >9) was associated with a lower mortality risk [hazard ratio 0.83 (95% confidence interval 0.74-0.92); P < .03). Each component of the SPPB test was also associated with mortality in univariate analysis, but only the SPPB balance test remained protective against mortality in multivariate analysis. Older age, lower handgrip strength and lower protein catabolic rate were associated with SPPB total scores <9, SPPB balance score and TUG time >10 s.ConclusionsScreening for frailty is crucial in chronic HD patients, and incorporating SPPB, especially the balance test, provides valuable insights. Diminished muscle strength and inadequate protein intake negatively influence the SPPB score and balance in chronic HD patients. Effective identification and management of frailty can therefore improve outcomes.Clinical trial registration clinicaltrialsgovNCT03845452.
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Project description:Sarcopenia and frailty are geriatric syndromes characterized by multisystem decline, which are related to and reflected by markers of skeletal muscle dysfunction. In older people, sarcopenia and frailty have been used for risk stratification, to predict adverse outcomes and to prompt intervention aimed at preventing decline in those at greatest risk. In this review, we examine sarcopenia and frailty in the context of chronic respiratory disease, providing an overview of the common assessments tools and studies to date in the field. We contrast assessments of sarcopenia, which consider muscle mass and function, with assessments of frailty, which often additionally consider social, cognitive and psychological domains. Frailty is emerging as an important syndrome in respiratory disease, being strongly associated with poor outcome. We also unpick the relationship between sarcopenia, frailty and skeletal muscle dysfunction in chronic respiratory disease and reveal these as interlinked but distinct clinical phenotypes. Suggested areas for future work include the application of sarcopenia and frailty models to restrictive diseases and population-based samples, prospective prognostic assessments of sarcopenia and frailty in relation to common multidimensional indices, plus the investigation of exercise, nutritional and pharmacological strategies to prevent or treat sarcopenia and frailty in chronic respiratory disease.
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Project description:Background: Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal the causal effect of circulating metabolites on frailty, sarcopenia and vascular aging related traits and diseases through a two-sample Mendelian Randomization (MR) analysis. Methods: Exposures were 486 metabolites analyzed in a genome-wide association study (GWAS), while outcomes included frailty, sarcopenia, arterial stiffness, atherosclerosis, peripheral vascular disease (PAD) and aortic aneurysm. Primary causal estimates were calculated using the inverse-variance weighted (IVW) method. Methods including MR Egger, weighted median, Q-test, and leave-one-out analysis were used for the sensitive analysis. Results: A total of 125 suggestive causative associations between metabolites and outcomes were identified. Seven strong causal links were ultimately identified between six metabolites (kynurenine, pentadecanoate (15:0), 1-arachidonoylglycerophosphocholine, androsterone sulfate, glycine and mannose) and three diseases (sarcopenia, PAD and atherosclerosis). Besides, metabolic pathway analysis identified 13 significant metabolic pathways in 6 age-related diseases. Furthermore, the metabolite-gene interaction networks were constructed. Conclusion: Our research suggested new evidence of the relationship between identified metabolites and 6 age-related diseases, which may hold promise as valuable biomarkers.
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