Biomarkers Of Sarcopenia Research Articles

Therapeutic strategies to modulate gut microbial health: Approaches for sarcopenia management.

Sarcopenia is a progressive and generalized loss of skeletal muscle and functions associated with ageing with currently no definitive treatment. Alterations in gut microbial composition have emerged as a significant contributor to the pathophysiology of multiple diseases. Recently, its association with muscle health has pointed to its potential role in mediating sarcopenia. The current review focuses on the association of gut microbiota and mediators of muscle health, connecting the dots between the influence of gut microbiota and their metabolites on biomarkers of sarcopenia. It further delineates the mechanism by which the gut microbiota affects muscle health with progressing age, aiding the formulation of a multi-modal treatment plan involving nutritional supplements and pharmacological interventions along with lifestyle changes compiled in the review. Nutritional supplements containing proteins, vitamin D, omega-3 fatty acids, creatine, curcumin, kefir, and ursolic acid positively impact the gut microbiome. Dietary fibres foster a conducive environment for the growth of beneficial microbes such as Bifidobacterium, Faecalibacterium, Ruminococcus, and Lactobacillus. Probiotics and prebiotics act by protecting against reactive oxygen species (ROS) and inflammatory cytokines. They also increase the production of gut microbiota metabolites like short-chain fatty acids (SCFAs), which aid in improving muscle health. Foods rich in polyphenols are anti-inflammatory and have an antioxidant effect, contributing to a healthier gut. Pharmacological interventions like faecal microbiota transplantation (FMT), non-steroidal anti-inflammatory drugs (NSAIDs), ghrelin mimetics, angiotensin-converting enzyme inhibitors (ACEIs), and butyrate precursors lead to the production of anti-inflammatory fatty acids and regulate appetite, gut motility, and microbial impact on gut health. Further research is warranted to deepen our understanding of the interaction between gut microbiota and muscle health for developing therapeutic strategies for ameliorating sarcopenic muscle loss.

From a solitary blood-derived biomarker to combined biomarkers of sarcopenia: Experiences from the Korean Frailty and Aging Cohort Study.

Sarcopenia is recognized as a complex and multifactorial disorder that includes nutritional deficiency, inactivity, proinflammatory status, hormonal changes, neurological degeneration, and metabolic disturbances. Its' pathogenesis is not fully understood. Therefore, identifying specific biomarkers of sarcopenia will help us understand its pathophysiology. The most frequently reported blood-derived biomarkers of sarcopenia are growth factors, neuromuscular junctions, endocrine systems, mitochondrial dysfunction, inflammation-mediated and redox processes, muscle protein turnover, blood metabolomics, and behavior-mediated biomarkers. Here, we address the implications of sarcopenia biomarkers based on our research experience with KFACS cohort data. It includes free testosterone, myostatin, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF-15), procollagen type III N-terminal peptide (P3NP), creatinine-based biomarkers, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), brain-derived neurotrophic factor (BDNF), metabolites (proline, alanine, tryptophan), and multi-biomarker risk score. We attempted to explain the paradoxical findings of myostatin and FGF-21 levels in relation to sarcopenia. GDF-15 levels were associated with sarcopenia prevalence but not its incidence. Plasma P3NP and BDNF levels may be biomarkers of muscle quality rather than quantity. Lower erythrocyte EPA and DHA levels were associated with slow gait speed, and erythrocyte EPA levels were associated with low handgrip strength. We developed a multi-biomarker risk score for sarcopenia and found that its accuracy in diagnosing sarcopenia was higher than that of any single biomarker.

Low Serum Alanine Aminotransferase Blood Activity Is Associated with Shortened Survival of Renal Cell Cancer Patients and Survivors: Retrospective Analysis of 1830 Patients

Background: Sarcopenia is characterized by a loss of muscle mass and function and is often associated with frailty, a syndrome linked to physical disability and shortened survival in various patient populations, including cancer patients. Low serum alanine aminotransferase (ALT) values, serving as a biomarker for sarcopenia, were previously associated with frailty and shortened survival in several cancers. In the current study, we aimed to test the association between low ALT and shorter survival in renal cell carcinoma (RCC) patients and survivors. Methods: This was a retrospective analysis of RCC patients and survivors, both in- and outpatients. We defined patients with sarcopenia as those presenting with ALT < 17 IU/L. Results: We identified records of 3012 RCC patients. The cohort included 1830 patients (mean age 65.6 ± 13.3 years, 68% were men) of whom only 179 underwent surgical treatment. Out of the eligible cohort, 811 patients (44.3%) had ALT < 17 IU/L, with a mean ALT value of patients within the low-ALT group of 11.79 IU/L, while the mean value in the higher ALT level group was 24.44 IU/L (p < 0.001). Patients in the low-ALT group were older (67.9 vs. 63.7 years; p < 0.001) and had lower BMIs (26.6 vs. 28; p < 0.001). In addition, patients with low ALT had lower hemoglobin values (12.14 vs. 12.91 g/dL; p < 0.001), higher serum creatinine (1.49 vs. 1.14; p < 0.001) and higher platelet to lymphocyte ratios (178 vs. 156; p < 0.001). In a univariate analysis, low ALT levels were associated with a 72% increase in mortality (95% CI 1.46–2.02, p < 0.001). In a multivariate model controlled for age, gender, hemoglobin, platelets, LDH, neutrophil to lymphocyte ratios and platelet to lymphocyte ratios, low ALT levels were still associated with a 27% increase in mortality (HR = 1.27, 95% CI 1.08–1.51; p = 0.005). Conclusion. Low ALT values, associated with sarcopenia and frailty, are also associated with shortened survival in RCC patients, and survivors and could potentially be applied for optimizing individual treatment decisions.

Circulating small non-coding RNA profiling for identification of older adults with low muscle strength and physical performance: A preliminary study

BackgroundSmall non-coding RNAs (ncRNAs) have recently emerged as potential biomarkers of sarcopenia. However, previous studies have rarely explored the association of small ncRNAs with sarcopenic components, especially muscle strength and physical performance. We aimed to examine circulating small ncRNA profiles to detect low muscle strength and physical performance in older adults. MethodsNinety-eight older adults were randomly selected from Korean Frailty and Aging Cohort Study and classified into the “Normal,” “Low muscle strength (MS) only,” “Low physical performance (PP) only,” and “Low MS and PP” groups by Asian Working Group for Sarcopenia 2019 criteria. We used high-throughput sequencing to delineate small ncRNA profiles in plasma. Differentially expressed small ncRNAs were analyzed to reveal distinct patterns based on muscle strength and physical performance status. ResultsIn “Low MS and PP” group, 119 miRNAs, 86 piRNAs, 92 snoRNAs, 106 snRNAs, and 15 tRNAs were differentially expressed compared to “Normal” group (p < 0.05). After Benjamini-Hochberg adjustment, 39 miRNAs, 2 piRNAs, 75 snoRNAs, 48 snRNAs, and 15 tRNAs showed differential expression in “Low MS and PP” group compared to than “Normal” group (adjusted p < 0.05). No significant differences were observed in comparisons between the other groups (adjusted p > 0.05). ConclusionThe expression of circulating small ncRNAs were comprehensively characterized, revealing distinct signatures in older adults with both low muscle strength and physical performance compared to normal individuals. Although preliminary, this characterization can advance small ncRNA research on age-related declines in muscle strength and physical performance by providing foundational data for further investigation.

Elevated serum levels of C-terminal agrin fragment in acetylcholine receptor antibody-positive myasthenia gravis

Agrin is essential for neuromuscular junction (NMJ) formation and maintenance. The C-terminal agrin fragment (CAF), generated by neurotrypsin-mediated cleavage of agrin, has been gaining attention as a potential biomarker for sarcopenia. We investigated serum CAF levels in myasthenia gravis (MG), a NMJ disorder. Compared to healthy controls, serum CAF levels were significantly elevated in acetylcholine receptor antibody-positive MG (AChR-MG) patients, but not in muscle-specific kinase antibody-positive MG patients. In AChR-MG, baseline and post-treatment CAF levels inversely correlated with post-treatment MG activities of daily living scores, suggesting that elevated CAF levels may reflect protective mechanisms against AChR-MG pathogenesis, such as improved NMJ regeneration.

Sphingolipid metabolites as potential circulating biomarkers for sarcopenia in men.

Sarcopenia is an age-related progressive loss of muscle mass and function. Sarcopenia is a multifactorial disorder, including metabolic disturbance; therefore, metabolites may be used as circulating biomarkers for sarcopenia. We aimed to investigate potential biomarkers of sarcopenia using metabolomics. After non-targeted metabolome profiling of plasma from mice of an aging mouse model of sarcopenia, sphingolipid metabolites and muscle cells from the animal model were evaluated using targeted metabolome profiling. The associations between sphingolipid metabolites identified from mouse and cell studies and sarcopenia status were assessed in men in an age-matched discovery (72 cases and 72 controls) and validation (36 cases and 128 controls) cohort; women with sarcopenia (36 cases and 36 controls) were also included as a discovery cohort. Both non-targeted and targeted metabolome profiling in the experimental studies showed an association between sphingolipid metabolites, including ceramides (CERs) and sphingomyelins (SMs), and sarcopenia. Plasma SM (16:0), CER (24:1), and SM (24:1) levels in men with sarcopenia were significantly higher in the discovery cohort than in the controls (all P<0.05). There were no significant differences in plasma sphingolipid levels for women with or without sarcopenia. In men in the discovery cohort, an area under the receiver-operating characteristic curve (AUROC) of SM (16:0) for low muscle strength and low muscle mass was 0.600 (95% confidence interval [CI]: 0.501-0.699) and 0.647 (95% CI: 0.557-0.737). The AUROC (95% CI) of CER (24:1) and SM (24:1) for low muscle mass in men was 0.669 (95% CI: 0.581-0.757) and 0.670 (95% CI: 0.582-0.759), respectively. Using a regression equation combining CER (24:1) and SM (16:0) levels, a sphingolipid (SphL) score was calculated; an AUROC of the SphL score for sarcopenia was 0.712 (95% CI: 0.626-0.798). The addition of the SphL score to HGS significantly improved the AUC from 0.646 (95% CI: 0.575-0.717; HGS only) to 0.751 (95% CI: 0.671-0.831, P=0.002; HGS+SphL) in the discovery cohort. The predictive ability of the SphL score for sarcopenia was confirmed in the validation cohort (AUROC=0.695, 95% CI: 0.591-0.799). SM (16:0), reflecting low muscle strength, and CER (24:1) and SM (16:0), reflecting low muscle mass, are potential circulating biomarkers for sarcopenia in men. Further research on sphingolipid metabolites is required to confirm these results and provide additional insights into the metabolomic changes relevant to the pathogenesis and diagnosis of sarcopenia.

Novel metabolic and lipidomic biomarkers of sarcopenia.

The pathophysiology of sarcopenia is complex and multifactorial and has not been fully elucidated. The impact of resistance training and nutritional support (RTNS) on metabolomics and lipodomics in older adults with sarcopenia remains uncertain. This study aimed to explore potential biomarkers of sarcopenia and clinical indicators of RTNS in older sarcopenic adults. Older individuals diagnosed with sarcopenia through routine health checkups at a community hospital were recruited for a 12-week randomized controlled trial focusing on RTNS. Plasma metabolomic and lipidomic profiles of 45 patients with sarcopenia and 47 matched controls were analysed using 1H-nuclear magnetic resonance (1H-NMR) and liquid chromatography-mass spectrometer (LC-MS). At baseline, the patient and control groups had similar age, sex, and height distribution. The patient group had significantly lower weight, BMI, grip strength, gait speed, skeletal muscle index, lean mass of both the upper and lower limbs, and lower limb bone mass. There was a significant difference in 12 metabolites between the control and patient groups. They are isoleucine (patient/control fold change [FC]=0.86±0.04, P=0.0005), carnitine (FC=1.05±0.01, P=0.0110), 1-methylhistamine/3-methylhistamine (FC=1.24±0.14, P=0.0039), creatinine (FC=0.71±0.04, P<0.0001), carnosine (FC=0.71±0.04, P=0.0007), ureidopropionic acid (FC=0.61±0.10, P=0.0107), uric acid (FC=0.88±0.03, P=0.0083), PC (18:2/20:0) (FC=0.69±0.03, P=0.0010), PC (20:2/18:0) (FC=0.70±0.06, P=0.0014), PC (18:1/20:1) (FC=0.74±0.05, P=0.0015), PI 32:1 (FC=4.72±0.17, P=0.0006), and PI 34:3 (FC=1.88±0.13, P=0.0003). Among them, carnitine, 1-methylhistamine/3-methylhistamine, creatinine, ureidopropionic acid, uric acid, PI 32:1, and PI 34:3 were first identified. Notably, PI 32:1 had highest diagnostic accuracy (0.938) for sarcopenia. 1-Methylhistamine/3-methylhistamine, carnosine, PC (18:2/20:0), PI 32:1, and PI 34:3 levels were not different from the control group after RTNS. These metabolites are involved in amino acid metabolism, lipid metabolism, and the PI3K-AKT/mTOR signalling pathway through the ingenuity pathway analysis. These findings provide information on metabolic changes, lipid perturbations, and the role of RTNS in patients with sarcopenia. They reveal new insights into its pathological mechanisms and potential therapies.

Disturbed carnitine metabolism is independently correlated with sarcopenia and prognosis in patients on hemodialysis

Background & AimsSarcopenia is frequent in hemodialysis patients and associated with an increased likelihood of adverse outcomes. Early identification of the risk of sarcopenia and effective intervention are of great importance for dialysis patients. However, little research has been carried out on potential biomarkers of sarcopenia in hemodialysis patients. The aim of this study was to investigate whether serum carnitine or acylcarnitine levels are biomarkers of sarcopenia in hemodialysis patients, and whether these are prognostic factors for occurrence of complications. MethodsThis prospective clinical pilot study enrolled patients (n=259) who were treated in the Blood Purification Center from May 2021 to July 2022, all participants were followed-up for 1- year. Serum carnintine and acylcarnitine (AC) were measured using our previously reported targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The correlations between carnitine or acylcarnitine levels with sarcopenia and prognosis in patients were analysed. ResultsThe C0 (Free carnitine, FC) and total carnitine (TC) levels were significantly lower in the sarcopenia group than in the nonsarcopenia group (nonsarcopenia vs. sarcopenia: 20.97 (16.96, 25.83) vs. 17.77 (14.30, 22.78); p =0.002) and (nonsarcopenia vs. sarcopenia: 30.12 (24.76, 36.62) vs. 26.03 (21.30, 32.01); p = 0.003). Besides, significant difference between the groups were noted in low free carnitine (C0 < 20 μmol/L) patients (nonsarcopenia vs. sarcopenia: 72 (42.4%) vs. 56 (62.9%); p = 0.002) and high C2/ C0 ratio (> 0.4) patients (nonsarcopenia vs. sarcopenia: 36 (21.2%) vs. 30 (33.7%); p = 0.028). By multivariable analysis, the disturbed CM defined as C0 deficient and/or C2/C0 carnitine ratio abnormal rise was independently and significantly correlated with the prevalence of sarcopenia after adjusting for some confounding factors, such as age, gender and dialysis duration (P values for trend <0.05).Hemodialysis patients with sarcopenia [OR: 3.214 (1.307,7.904)] and disturbed CM [OR: 3.217 (1.112,9.305)] both had a 3-fold increased risk of falling and fracture after one year follow up. In addition, age and sarcopenia [OR: 2.883 (1.321, 6.289)] were independently and positively associated with incidence of Cardio- and cerebro-vascular events. ConclusionDisturbed carnitine metabolism is independently correlated with sarcopenia and prognosis in patients with hemodialysis. Serum carnitine level and C0/C2 ratio has the potential to be a simple, objective, and quick test for sarcopenia assessment whether such an intervention should be carried out for dialysis patients.

Machine Learning-Based Identification of Diagnostic Biomarkers for Korean Male Sarcopenia Through Integrative DNA Methylation and Methylation Risk Score: From the Korean Genomic Epidemiology Study (KoGES).

Sarcopenia, characterized by a progressive decline in muscle mass, strength, and function, is primarily attributable to aging. DNA methylation, influenced by both genetic predispositions and environmental exposures, plays a significant role in sarcopenia occurrence. This study employed machine learning (ML) methods to identify differentially methylated probes (DMPs) capable of diagnosing sarcopenia in middle-aged individuals. We also investigated the relationship between muscle strength, muscle mass, age, and sarcopenia risk as reflected in methylation profiles. Data from 509 male participants in the urban cohort of the Korean Genome Epidemiology Study_Health Examinee study were categorized into quartile groups based on the sarcopenia criteria for appendicular skeletal muscle index (ASMI) and handgrip strength (HG). To identify diagnostic biomarkers for sarcopenia, we used recursive feature elimination with cross validation (RFECV), to pinpoint DMPs significantly associated with sarcopenia. An ensemble model, leveraging majority voting, was utilized for evaluation. Furthermore, a methylation risk score (MRS) was calculated, and its correlation with muscle strength, function, and age was assessed using likelihood ratio analysis and multinomial logistic regression. Participants were classified into two groups based on quartile thresholds: sarcopenia (n = 37) with ASMI and HG in the lowest quartile, and normal ranges (n = 48) in the highest. In total, 238 DMPs were identified and eight probes were selected using RFECV. These DMPs were used to build an ensemble model with robust diagnostic capabilities for sarcopenia, as evidenced by an area under the receiver operating characteristic curve of 0.94. Based on eight probes, the MRS was calculated and then validated by analyzing age, HG, and ASMI among the control group (n = 424). Age was positively correlated with high MRS (coefficient, 1.2494; odds ratio [OR], 3.4882), whereas ASMI and HG were negatively correlated with high MRS (ASMI coefficient, -0.4275; OR, 0.6521; HG coefficient, -0.3116; OR, 0.7323). Overall, this study identified key epigenetic markers of sarcopenia in Korean males and developed a ML model with high diagnostic accuracy for sarcopenia. The MRS also revealed significant correlations between these markers and age, HG, and ASMI. These findings suggest that both diagnostic models and the MRS can play an important role in managing sarcopenia in middle-aged populations.

GDF-15 is associated with sarcopenia and frailty in acutely admitted older medical patients.

Growth differentiation factor-15 (GDF-15) has been associated with senescence, lower muscle strength, and physical performance in healthy older people. Still, it is not clear whether GDF-15 can be utilized as a biomarker of sarcopenia and frailty in the early stages of hospitalization. We investigated the association of plasma GDF-15 with sarcopenia and frailty in older, acutely admitted medical patients. The present study is based on secondary analyses of cross-sectional data from the Copenhagen PROTECT study, a prospective cohort study including 1071 patients ≥65years of age admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg, Denmark. Muscle strength was assessed using handgrip strength, and lean mass was assessed using direct segmental multifrequency bioelectrical impedance analyses and used to clarify the potential presence of sarcopenia defined according to guidelines from the European Working Group on Sarcopenia in Older People. Frailty was evaluated using the Clinical Frailty Scale. Plasma GDF-15 was measured using electrochemiluminescence assays from Meso Scale Discovery (MSD, Rockville, MD, USA). We included 1036 patients with completed blood samples (mean age 78.9±7.8years, 53% female). The median concentration of GDF-15 was 2669.3pg/mL. Systemic GDF-15 was significantly higher in patients with either sarcopenia (P<0.01) or frailty (P<0.001) compared with patients without the conditions. Optimum cut-off points of GDF-15 relating to sarcopenia and frailty were 1541 and 2166pg/mL, respectively. Systemic GDF-15 was higher in acutely admitted older medical patients with sarcopenia and frailty compared with patients without. The present study defined the optimum cut-off for GDF-15, related to the presence of sarcopenia and frailty, respectively. When elevated above the derived cutoffs, GDF-15 was strongly associated with frailty and sarcopenia in both crude and fully adjusted models.

Appendicular lean mass and the risk of stroke and Alzheimer’s disease: a mendelian randomization study

BackgroundAppendicular lean mass (ALM) is a good predictive biomarker for sarcopenia. And previous studies have reported the association between ALM and stroke or Alzheimer’s disease (AD), however, the causal relationship is still unclear, The purpose of this study was to evaluate whether genetically predicted ALM is causally associated with the risk of stroke and AD by performing Mendelian randomization (MR) analyses.MethodsA two-sample MR study was designed. Genetic variants associated with the ALM were obtained from a large genome-wide association study (GWAS) and utilized as instrumental variables (IVs). Summary-level data for stroke and AD were generated from the corresponding GWASs. We used random-effect inverse-variance weighted (IVW) as the main method for estimating causal effects, complemented by several sensitivity analyses, including the weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Multivariable analysis was further conducted to adjust for confounding factors, including body mass index (BMI), type 2 diabetes mellitus (T2DM), low density lipoprotein-C (LDL-C), and atrial fibrillation (AF).ResultsThe present MR study indicated significant inverse associations of genetically predicted ALM with any ischemic stroke ([AIS], odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89–0.97; P = 0.002) and AD (OR, 090; 95% CI 0.85–0.96; P = 0.001). Regarding the subtypes of AIS, genetically predicted ALM was related to the risk of large artery stroke ([LAS], OR, 0.86; 95% CI 0.77–0.95; P = 0.005) and small vessel stroke ([SVS], OR, 0.80; 95% CI 0.73–0.89; P < 0.001). Regarding multivariable MR analysis, ALM retained the stable effect on AIS when adjusting for BMI, LDL-C, and AF, while a suggestive association was observed after adjusting for T2DM. And the estimated effect of ALM on LAS was significant after adjustment for BMI and AF, while a suggestive association was found after adjusting for T2DM and LDL-C. Besides, the estimated effects of ALM were still significant on SVS and AD after adjustment for BMI, T2DM, LDL-C, and AF.ConclusionsThe two-sample MR analysis indicated that genetically predicted ALM was negatively related to AIS and AD. And the subgroup analysis of AIS revealed a negative causal effect of genetically predicted ALM on LAS or SVS. Future studies are required to further investigate the underlying mechanisms.

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.

Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated. the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed. c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively. our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

Irisin and Its Role in Postmenopausal Osteoporosis and Sarcopenia.

Menopause, an extremely delicate phase in a woman's life, is characterized by a drop in estrogen levels. This decrease has been associated with the onset of several diseases, including postmenopausal osteoporosis and sarcopenia, which often coexist in the same person, leading to an increased risk of fractures, morbidity, and mortality. To date, there are no approved pharmacological treatments for sarcopenia, while not all of those approved for postmenopausal osteoporosis are beneficial to muscles. In recent years, research has focused on the field of myokines, cytokines, or peptides secreted by skeletal muscle fibers following exercise. Among these, irisin has attracted great interest as it possesses myogenic properties but at the same time exerts anabolic effects on bone and could therefore represent the link between muscle and bone. Therefore, irisin could represent a new therapeutic strategy for the treatment of osteoporosis and also serve as a new biomarker of sarcopenia, thus facilitating diagnosis and pharmacological intervention. The purpose of this review is to provide an updated summary of what we know about the role of irisin in postmenopausal osteoporosis and sarcopenia.

DNA methylation of skeletal muscle function-related secretary factors identifies FGF2 as a potential biomarker for sarcopenia.

Sarcopenia is characterized by progressive loss of muscle mass and function due to aging. DNA methylation has been identified to play important roles in the dysfunction of skeletal muscle. The aim of our present study was to explore the whole blood sample-based methylation changes of skeletal muscle function-related factors in patients with sarcopenia. The overall DNA methylation levels were analysed by using MethlTarget™ DNA Methylation Analysis platform in a discovery set consistent of 50 sarcopenic older adults (aged ≥65years) and 50 age- and sex-matched non-sarcopenic individuals. The candidate differentially methylated regions (DMRs) were further validated by Methylation-specific PCR (MSP) in another two independent larger sets and confirmed by pyrosequencing. Receiver operating characteristic (ROC) curve analysis was used to determine the optimum cut-off levels of fibroblast growth factor 2 (FGF2)_30 methylation best predicting sarcopenia and area under the ROC curve (AUC) was measured. The correlation between candidate DMRs and the risk of sarcopenia was investigated by univariate analysis and multivariate logistic regression analysis. Among 1149 cytosine-phosphate-guanine (CpG) sites of 27 skeletal muscle function-related secretary factors, 17 differentially methylated CpG sites and 7 differentially methylated regions (DMRs) were detected between patients with sarcopenia and control subjects in the discovery set. Further methylation-specific PCR identified that methylation of fibroblast growth factor 2 (FGF2)_30 was lower in patients with sarcopenia and the level was decreased as the severity of sarcopenia increased, which was confirmed by pyrosequencing. Correlation analysis demonstrated that the methylation level of FGF2_30 was positively correlated to ASMI (r=0.372, P<0.001), grip strength (r=0.334, P<0.001), and gait speed (r=0.411, P<0.001). ROC curve analysis indicated that the optimal cut-off value of FGF2_30 methylation level that predicted sarcopenia was 0.15 with a sensitivity of 84.6% and a specificity of 70.1% (AUC=0.807, 95% CI=0.756-0.858, P<0.001). Multivariate logistic regression analyses showed that lower FGF2_30 methylation level (<0.15) was significantly associated with increased risk of sarcopenia even after adjustment for potential confounders including age, sex, and BMI (adjusted OR=9.223, 95% CI: 6.614-12.861, P<0.001). Our results suggest that lower FGF2_30 methylation is correlated with the risk and severity of sarcopenia in the older adults, indicating that FGF2 methylation serve as a surrogate biomarker for the screening and evaluation of sarcopenia.

Myostatin and Activin A as Biomarkers of Sarcopenia in Inflammatory Bowel Disease Patients.

The prevalence of sarcopenia in inflammatory bowel disease patients has received increasing attention. The aim of this study is to assess the usefulness of determining levels of myostatin (MSTN) and activin A (Act A) as potential markers of disease activity and occurrence of sarcopenia in Crohn's disease and ulcerative colitis patients. The case-control study included 82 patients with Inflammatory Bowel Disease. The control group consisted of 25 healthy volunteers. The serum levels of myostatin and activin A were determined by the quantitative sandwich enzyme-linked immunosorbent assay. Sarcopenia was diagnosed based on the EWGSOP2 criteria. The study found lower levels of myostatin and activin A in the IBD patients. There were significantly lower levels of myostatin (80.6 pg/mL vs. 186.2 pg/mL; p = 0.0364) as well as activin A (32.1 pg/mL vs. 35.2 pg/mL; p = 0.0132) in the IBD patients with sarcopenia compared to those without sarcopenia. Positive correlations were found between MSTN levels and Muscle Mass Index (rho = 0.31; p < 0.005) and hand grip strength (rho = 0.34, p < 0.05) in the IBD patients. The determination of serum levels of MSTN and Act A may be useful in the early diagnosis of sarcopenia in IBD patients.

Metabolic signatures and potential biomarkers of sarcopenia in suburb-dwelling older Chinese: based on untargeted GC–MS and LC–MS

BackgroundUntargeted metabolomics can be used to expand our understanding of the pathogenesis of sarcopenia. However, the metabolic signatures of sarcopenia patients have not been thoroughly investigated. Herein, we explored metabolites associated with sarcopenia by untargeted gas chromatography (GC)/liquid chromatography (LC)–mass spectrometry (MS) and identified possible diagnostic markers.MethodsForty-eight elderly subjects with sarcopenia were age and sex matched with 48 elderly subjects without sarcopenia. We first used untargeted GC/LC–MS to analyze the plasma of these participants and then combined it with a large number of multivariate statistical analyses to analyze the data. Finally, based on a multidimensional analysis of the metabolites, the most critical metabolites were considered to be biomarkers of sarcopenia.ResultsAccording to variable importance in the project (VIP > 1) and the p-value of t-test (p < 0.05), a total of 55 metabolites by GC–MS and 85 metabolites by LC–MS were identified between sarcopenia subjects and normal controls, and these were mostly lipids and lipid-like molecules. Among the top 20 metabolites, seven phosphatidylcholines, seven lysophosphatidylcholines (LysoPCs), phosphatidylinositol, sphingomyelin, palmitamide, L-2-amino-3-oxobutanoic acid, and palmitic acid were downregulated in the sarcopenia group; only ethylamine was upregulated. Among that, three metabolites of LysoPC(17:0), L-2-amino-3-oxobutanoic acid, and palmitic acid showed very good prediction capacity with AUCs of 0.887 (95% CI = 0.817–0.957), 0.836 (95% CI = 0.751–0.921), and 0.805 (95% CI = 0.717–0.893), respectively.ConclusionsThese findings show that metabonomic analysis has great potential to be applied to sarcopenia. The identified metabolites could be potential biomarkers and could be used to study sarcopenia pathomechanisms.

Complement component C3 is associated with body composition parameters and sarcopenia in community-dwelling older adults: a cross-sectional study in Japan

BackgroundChronic inflammation is a factor in the pathogenesis of sarcopenia, which is characterized by low muscle mass and reduced strength. Complement C3 is important in the management of the immune network system. This study seeks to determine the relationship between serum C3 levels and body composition and sarcopenia-related status in community-dwelling older adults.MethodsStudy participants were 269 older adults living in rural Japan. A bioelectrical impedance analysis device was used to measure body composition parameters including body mass index (BMI), body fat percentage, waist-hip-ratio, and appendicular skeletal muscle mass index (SMI). Muscle function was measured by handgrip strength and 6-m walking speed. The correlation coefficients for C3 level and measurements were calculated using Pearson correlation analysis. Participants were categorized into normal, pre-sarcopenia, dynapenia, or sarcopenia groups. Sarcopenia was defined according to 2019 Asian Working Group for Sarcopenia definition, dynapenia was defined as low muscle function without low muscle mass, and pre-sarcopenia was defined as the presence of low muscle mass only. The C3 threshold score for sarcopenia status was evaluated by receiver operating characteristic curve (ROC) analysis.ResultsSignificant positive correlations were found between C3 and BMI, body fat percentage, and waist-hip ratio in both sexes, and further positive correlations with SMI were found in women. The relationship with body fat percentage was particularly strong. Body composition measurements (BMI, body fat percentage, and waist- hip ratio) and C3 levels were lowest in the sarcopenia group compared with the others. ROC analysis showed that the significant threshold of C3 for discriminating between the normal and sarcopenia groups was 105 mg/dL. Multiple logistic regression analysis showed that participants with C3 < 105 mg/dL had an odds ratio of 3.27 (95% confidence interval, 1.49–7.18) for sarcopenia adjusted by sex, age and body fat percentage.ConclusionC3 levels are suggested to be related to body composition and pathophysiological functions of sarcopenia. C3 is expected to become a useful biomarker for sarcopenia, for predicting the onset of the disease and for predicting the effectiveness of interventions.

Identification of a novel biomarker for sarcopenia diagnosis using serum metabolomic analysis: a pilot study.

This pilot study compared serum metabolites in participants with and without sarcopenia. Metabolomic techniques were applied to identify serum metabolites and novel biomarkers specific to patients with sarcopenia. In accordance with AWGS2019 criteria, sarcopenia was defined as low muscle mass plus either low muscle strength/low physical function, and severe sarcopenia was defined as low muscle mass, low muscle strength, and low physical function all together. The sarcopenia group had higher hypoxanthine, galactose, and mannose levels but lower triethanolamine and homogentisic acid levels than the non-sarcopenia group. The severe sarcopenia group had lower levels of alpha-tocopherol than the mild and moderate sarcopenia groups. This study is the first to identify hypoxanthine as a potential biomarker for sarcopenia in humans and provides new insights into the pathophysiology of sarcopenia. Furthermore, the identified metabolites may be useful for the early detection of sarcopenia.

C‐Reactive Protein Level as a Novel Serum Biomarker in Sarcopenia

Background. The role of C‐reactive protein (CRP), an inflammatory marker, in the development of sarcopenia remains uncertain. Methods. This cross‐sectional research involved the enrollment of 207 patients, classified into two groups: 74 patients with sarcopenia and 133 patients without sarcopenia. Clinical data of the participants, including hand grip strength, walking speed, appendicular lean mass (ALM), and calf circumference, were collected and recorded. We evaluated the extent to which CRP levels are associated with the risk of sarcopenia using both univariate and multivariate logistic regression models. Besides, the correlation between CRP levels, hand grip strength, ALM, and walking speed was examined using the Spearman rank correlation test. Moreover, we have employed the Mendelian randomization (MR) analysis technique to explore the causal relationship between CRP levels and the occurrence of sarcopenia. Results. The sarcopenia group showed a higher proportion of older women, with significant differences in anemia prevalence, calf circumference, gait speed, ALM, hand grip strength, and elevated CRP levels compared to the control group. Logistic regression analyses identified CRP as an independent risk factor for sarcopenia (OR: 1.151, 95% CI:1.070−1.238, and P &lt; 0.001). Correlation analysis results revealed a noteworthy inverse association with hand grip strength (R = −0.454 and P &lt; 0.001), ALM (R = −0.426 and P &lt; 0.001), and walking speed (R = −0.431 and P &lt; 0.001). MR analysis provided further evidence of a significant detrimental link between genetically predicted CRP levels and essential sarcopenia characteristics, with consistent results across various statistical models. Conclusions. Our study uncovered strong evidence supporting a noteworthy inverse association and causality between CRP concentrations and sarcopenia, indicating that CRP has the potential to serve as a biomarker for sarcopenia.

Increased Serum Soluble (Pro)renin Receptor Levels in Patients with Sarcopenia

Purpose. Sarcopenia is an advancing and widespread skeletal muscle condition characterized by the depletion of skeletal muscle mass. The (pro)renin receptor ((P)RR) is a multifaceted protein with both pathophysiological and physiological functions. (P)RR is cleaved to generate soluble (P)RR, whose blood concentration may reflect the expression level of tissue (P)RR. We have discovered that the expression of (P)RR was elevated in the atrophied skeletal muscles of aged mice and humans. Methods. In this study, we examined the correlation between muscle atrophy and serum soluble (P)RR levels in bedridden patients with sarcopenia. Results. In total, 45 subjects were enrolled. Their ages were 81 (59–89) y.o., and serum soluble (P)RR levels were 30.5 ± 7.3 ng/ml. Lean body mass ratio (lean body mass/body weight), an index of muscle mass, was independently significantly and negatively correlated with serum soluble (P)RR concentrations in all patients. In addition, the lean body mass ratio was independently significantly and negatively correlated with serum soluble (P)RR concentrations in older patients (≥82 y.o.) but not in younger patients (&lt;82 y.o.). Conclusion. These data suggested that patients with sarcopenia, especially in elderly patients, may be associated with increased (P)RR expression. The serum soluble (P)RR level could be a biomarker of sarcopenia although this issue should be investigated by future studies.