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Original Article
Carnitine Metabolite as a Potential Circulating Biomarker for Sarcopenia in Men
Je Hyun Seo1*orcid, Jung-Min Koh2*orcid, Han Jin Cho3, Hanjun Kim3, Young‑Sun Lee3, Su Jung Kim4, Pil Whan Yoon5, Won Kim6, Sung Jin Bae7, Hong-Kyu Kim7, Hyun Ju Yoo4orcid, Seung Hun Lee2orcid

DOI: https://doi.org/10.3803/EnM.2024.2117
Published online: November 28, 2024

1Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Korea

2Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

3Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea

4Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea

5Department of Orthopedic Surgery, Seoul Now Hospital, Anyang, Korea

6Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

7Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Corresponding authors: Hyun Ju Yoo Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-4029, Fax: +82-2-3010-8566, E-mail: yoohyunju@amc.seoul.kr
Seung Hun Lee Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-5666, Fax: +82-2-3010-6962, E-mail: hun0108@amc.seoul.kr
*These authors contributed equally to this work.
• Received: July 28, 2024   • Revised: September 21, 2024   • Accepted: October 7, 2024

Copyright © 2024 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Background
    Sarcopenia, a multifactorial disorder involving metabolic disturbance, suggests potential for metabolite biomarkers. Carnitine (CN), essential for skeletal muscle energy metabolism, may be a candidate biomarker. We investigated whether CN metabolites are biomarkers for sarcopenia.
  • Methods
    Associations between the CN metabolites identified from an animal model of sarcopenia and muscle cells and sarcopenia status were evaluated in men from an age-matched discovery (72 cases, 72 controls) and a validation (21 cases, 47 controls) cohort.
  • Results
    An association between CN metabolites and sarcopenia showed in mouse and cell studies. In the discovery cohort, plasma C5-CN levels were lower in sarcopenic men (P=0.005). C5-CN levels in men tended to be associated with handgrip strength (HGS) (P=0.098) and were significantly associated with skeletal muscle mass (P=0.003). Each standard deviation increase in C5-CN levels reduced the odds of low muscle mass (odd ratio, 0.61; 95% confidence interval [CI], 0.42 to 0.89). The area under the receiver operating characteristic curve (AUROC) of CN score using a regression equation of C5-CN levels, for sarcopenia was 0.635 (95% CI, 0.544 to 0.726). In the discovery cohort, addition of CN score to HGS significantly improved AUROC from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810; P=0.006; HGS+CN score). The improvement was confirmed in the validation cohort (AUROC=0.563; 95% CI, 0.470 to 0.656 for HGS; and AUROC=0.712; 95% CI, 0.569 to 0.855 for HGS+CN score; P=0.027).
  • Conclusion
    C5-CN, indicative of low muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies are required to confirm these results and explore sarcopenia-related metabolomic changes.
  • Keywords: Aging; Metabolomics; Sarcopenia; Biomarkers; Carnitine
Sarcopenia is characterized by a decline in muscle mass, muscle strength, and physical performance with age [1-3]. Such decline can lead to various adverse outcomes, such as falls, fractures, frailty, functional decline, and mortality [1-3]. Accordingly, sarcopenia has emerged as a major health concern. Increased life expectancy and sedentary lifestyle in modern society have elevated the prevalence of sarcopenia, resulting in a substantial economic burden [4]. Currently, no specific drugs have been approved for the treatment of sarcopenia, and the therapeutic effects of exercise and nutritional supplementation are limited once sarcopenia has progressed [3]; therefore, detecting sarcopenia at an early stage is important for its management.
To diagnose sarcopenia, a combination of assessments of muscle mass, muscle strength, and functional performance, must be conducted using various modalities [1-3]. However, these clinical assessments mainly reflect the skeletal muscle status as a static indicator at a slightly advanced state. Muscle, a highly active metabolic organ in the human body, causes changes in energy metabolism that directly contribute to age-related changes in the skeletal muscle during the early stages of sarcopenia [5]. Given that metabolites represent the downstream changes in the expression of genome, transcriptome, and proteome, metabolomics has emerged as a promising approach to reveal inherent omics variations closest to the disease risk/phenotype, particularly with recent advances in liquid chromatography-tandem mass spectrometry (LC-MS/MS) [6]. Accordingly, metabolites may be used as early diagnostic biomarkers for sarcopenia.
In this study, we focused on carnitine (CN) levels as a potential biomarker of sarcopenia. CN, an amino acid derivative, plays an important role in energy metabolism in cardiac and skeletal muscles by maintaining mitochondrial function through the transport of long-chain fatty acids into mitochondria for fatty acid oxidation [7-9] and detoxification via the removal of toxic acyl compounds [10]. Metabolic pathway dysfunctions in mitochondria are reportedly related to reduced muscle mass and loss of strength [11]. Considering the important role of muscle metabolism, CN has been hypothesized to be a biomarker of sarcopenia. In fact, the potential of circulating CN levels as a biomarker for muscle mass has been reported for various disorders, such as chronic kidney disease [12], cancer cachexia [13], gastrointestinal cancer [14], and heart failure [15]. Recently, some studies revealed the association of CN levels with some parameters of age-related sarcopenia, including thigh muscle cross-sectional area [16], appendicular skeletal muscle mass (ASM) [17], the skeletal muscle mass index (SMI) [18], handgrip strength (HGS) [18], gait speed [18], and physical performance [19,20]. However, the clinical applicability of plasma CN levels as a biomarker of age-related sarcopenia remains uncertain.
We aimed to investigate whether plasma CN metabolites are biomarkers of sarcopenia. To this end, we conducted metabolomic studies designed in two phases: (1) targeted metabolomics of CN using an aging mouse model of sarcopenia and muscle cells and (2) targeted metabolomics using the plasma of elderly men with sarcopenia and age-matched controls in two independent cohorts, the discovery cohort and validation cohort, to confirm the results from the phase 1 study.
Experimental studies

Aging mouse model of sarcopenia

As aging is the main risk factor for sarcopenia, the natural aging mouse model of sarcopenia, which has been widely used in the study of sarcopenia [21], was used in the present study. Male C57BL/6 mice were purchased from the Korea Research Institute of Bioscience and Biotechnology (Daejeon, Korea). Most natural aging mouse models of sarcopenia comprise mice older than 18 months [21]; therefore, mice aged 7 and 19 months, reflecting young and old age in humans, were used. All mice were housed in an environmentally controlled, pathogen-free room under a 12-hour light/12-hour dark cycle, with unrestricted access to laboratory chow and water. After 4 hours of fasting, mice were euthanized via cardiac puncture under anesthesia induced by an intraperitoneal injection of 50 mg/kg Zoletil 50 (Virbac, Carros, France) and 10 mg/kg Rompun (Bayer Korea, Seoul, Korea). Relative muscle mass (%) was defined as the weight of the isolated muscle as a percentage of total body weight. All animal care procedures were reviewed and approved by the Institutional Animal Care and Use Committee of the Asan Institute for Life Sciences (No. 2016-12-035).

Differentiation of muscle cells

Murine C2C12 myoblasts (MBs) were purchased from the American Type Culture Collection (Rockville, MD, USA) and cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (Gibco, Grand Island, NY, USA), 100 U/mL penicillin, and 0.1 mg/mL streptomycin. Cells were maintained in a humidified CO2 incubator at 37°C. To induce differentiation, C2C12 MBs were exposed to DMEM, containing 2% horse serum, for 2 days (myocytes [MCs]) or 6 days (myotubes [MTs]). MBs, MCs, or MTs were incubated in serum-free DMEM for 24 hours. The 24 hour-conditioned medium (CM) was collected, and total cell lysates were prepared using a radioimmunoprecipitation buffer.
Human cohort study

Study participants

Two independent case-control studies were approved by the Institutional Review Board of Veterans Health Service Medical Center (IRB No. 2020-02-015) and Asan Medical Center (AMC; IRB No. 2017-0553) and were conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment.
In the discovery cohort, participants ≥65 years, who visited the Division of Endocrinology, Department of Internal Medicine, Veterans Health Service Medical Center (Seoul, Korea) to undergo comprehensive geriatric assessment between August 2020 and March 2021, were enrolled in the “Veterans Sarcopenia Study” [22]. Before the commencement of the study, all participants completed questionnaires, which included questions about medical history, EuroQol Visual Analogue Scale (EQ-VAS), Strength, Assistance in walking, Rising from a chair, Climbing stairs, Falls (SARC-F), and underwent muscle mass measurement, muscle strength test, and blood sampling.
In the validation cohort, patients who visited the AMC (Seoul, Korea) to undergo comprehensive assessment for musculoskeletal disorders between May 2017 and March 2020, were enrolled. Before the study, all participants completed questionnaires (including medical history), underwent muscle mass measurement, muscle strength test, and blood sampling. Remnants of human muscle tissue from orthopedic surgeries were obtained from some participants in the validation cohort.

Assessment of sarcopenia

In both the discovery and validation cohorts, body composition was evaluated using bioelectrical impedance analysis (InBody 570, Biospace Co., Seoul, Korea). ASM was calculated as the sum of muscle mass in the arms and legs, and the SMI was calculated by dividing ASM by the square of the participant’s height, ensuring an objective comparison of muscle mass between participants. Muscle strength was measured as HGS using a digital hand dynamometer (T.K.K 5401, Takei, Tokyo, Japan). Participants were asked to stand with their forearm fully extended away from the body at thigh level and were then instructed to exert maximum grip strength twice with both their left and right hands. The dominant hand for this activity was recorded. In this study, low muscle mass was defined as SMI <7.0 kg/m2 for men and low muscle strength was defined as HGS <28 kg for men, according to the consensus of the Asian Working Group for Sarcopenia 2019 [1]. When a conflict was found between SMI and HGS, the SMI was prioritized for classification.
Participants with life expectancy of less than 1 year due to malignancy. Participants with chronic diseases (such as heart failure, stroke, Alzheimer’s disease, nutrition intake problem, or chronic kidney disease) and those using medications (such as glucocorticoid) that could affect muscle mass and function were excluded. In the discovery cohort, after excluding ineligible participants, blood samples were collected from 313 eligible participants in the Veterans Sarcopenia Study cohort [22]. For each case, controls were matched in a 1:1 ratio for age within a ± 2-year range. In the validation cohort, controls were matched according to a 2-year age difference for each case.

Targeted profiling of carnitine in samples obtained from mice, cell cultures, human plasma, and human muscle tissues

Muscle samples (20 to 30 mg) were homogenized with Tissue-Lyzer (Qiagen, Hilden, Germany) before the addition of an internal standard solution. After quick, sequential washes with phosphate-buffered saline and H2O, approximately 1 million cells were harvested with 1.4 mL cold methanol/H2O (4/1, v/v) and lysed via vigorous vortexing. For acyl CN, a 50 μL volume of 10 nM C16-L-carnitine-d3-HCL was added to the cell lysate. CN metabolites were determined using a LC-MS/MS system equipped with a 1290 HPLC system (Agilent, Waldbronn, Germany) and a QTRAP 5500 (AB Sciex, Toronto, ON, Canada).
The Zorbax HILIC (2.1×100 mm) column (Agilent Technologies, Santa Clara, CA, USA) was used for the experiment. Mobile phase A comprised acetonitrile/water/100 mM ammonium formate (pH 3.2) at a ratio of 50:45:5 (v/v), while mobile phase B comprised acetonitrile/water/100 mM ammonium formate (pH 3.2) at a ratio of 90:5:5 (v/v). The following separation gradient was employed: 95 to 0% of B for 7 minutes, hold at 0% of B for 3 minutes, 0 to 95% of B for 2 minutes, and hold at 95% of B for 3 minutes. The liquid chromatography flow rate was 300 μL/min, and column temperature was kept at 35℃. Multiple reaction monitoring was performed in the positive ion mode. Data analysis was performed using Analyst version 1.5.2 software (ABSciex, Flamingham, MA, USA). Multiple reaction monitoring was performed in the positive ion mode, and the extracted ion chromatogram (EIC) corresponding to the specific transition for each analyte was used for quantification. Area under the curve of each EIC was normalized to that of the internal standard. The calibration range for each lipid was 0.1 to 10,000 nM (r2≥0.99).
Data analysis was performed using Analyst version 1.5.2 software. For the CM and cell lysates, lipid concentration was normalized to the total protein concentration. CN levels in 50 μL human plasma were quantified as described above.
Statistical analysis
Data are presented as mean±standard deviation (SD) for normally distributed continuous variables, median (interquartile range) for non-normally distributed continuous variables, or number (%) for categorical variables. We used Student’s t test for normally distributed continuous variables or Mann-Whitney U test for non-normally distributed continuous variables. For categorical variables, we used the chi-square test or Fisher’s exact test for categorical variables. A P<0.05 from the Kolmogorov-Smirnov test for normality assessment indicated non-normal distribution. Log-transformed CN levels were used due to skewed distribution. Pearson correlation analysis for CN levels with normal distribution or Spearman’s correlation analysis for CN levels with non-normal distribution was used to examine the relation between CN concentrations and relative muscle mass, HGS, and SMI. The associations between CN levels and sarcopenia parameters (SMI and HGS) were investigated using linear regression analyses. Logistic regression analyses were performed to generate odds ratios (ORs) with a 95% confidence interval (CI). We calculated the CN score, a diagnostic regression equation for sarcopenia, based on linear regression analysis with SMI or HGS in discovery cohort to evaluate the predictive potential of CN metabolites. Receiver operating characteristic (ROC) curve analysis was performed, and the area under the receiver operating characteristic curve (AUROC) was calculated to evaluate the potential CN levels for predicting sarcopenia. The cutoff values for CN levels were determined through ROC curve analysis to establish the optimal threshold for distinguishing between sarcopenia and non-sarcopenia. All statistical analyses were performed using the R version 4.2.2 program (R Foundation, Vienna, Austria), with P<0.05 indicating statistical significance.
Carnitine levels in the muscle and plasma of mice
Despite higher body weights, absolute muscle weights and relative muscle mass were significantly lower in aged mice than in young mice (both P<0.05) (Supplemental Table S1). Aged mice exhibited significantly lower plasma C4-, C5-, and C6-CN levels than young mice (all, P<0.05) (Table 1). Plasma C2-, C3-, C8-, and C16-CN levels tended to be lower in aged mice than in young mice (all, P<0.100). Plasma C2-, C3-, C4-, C5-, and C6-CN levels were positively associated with relative muscle mass (r=0.493–0.676, P=0.003–0.044, respectively). There were no significant differences in muscle CN content between aged mice and young mice (Supplemental Table S2). Muscle C5-CN was positively associated with relative muscle mass (r=0.578, P=0.017; data not shown).
Carnitine levels in differentiating muscle cells
C5- and C6-CN levels in the cell lysate decreased during differentiation (all P<0.05) (Fig. 1). C10-, C12-, C14-, C16-, C18-, and C18:1-CN levels were significantly lower in MT than in MB (all P<0.05) (Fig. 1). C0-, C2, C3-, C4-, C12-, and C14-CN levels were only measured in the CM; however, no significant difference was observed (data not shown).
Characteristics of the study participants in the discovery cohort
The main characteristics of 144 men in the discovery cohort (72 men with sarcopenia as cases and 72 age-matched men without sarcopenia as controls) from the Veterans Sarcopenia Study are presented in Table 2. Age did not significantly differ between the case and control groups (P=0.989). The weight, height, and body mass index of the sarcopenia group were significantly lower than those of the control group (all P<0.001). Muscle mass parameters (lean mass, ASM, and SMI) and HGS of the case group were significantly lower than those of the control group (all P<0.001). The SARC-F value of the sarcopenia group was significantly higher than that of the control group (P=0.005), and the EQ-VAS score of the sarcopenia group was significantly lower than that of the control group (P<0.001). No significant differences were observed in the chair stand test score, drinking and exercise habits, and prevalence of hypertension and diabetes between the case and control groups (all P>0.05).
Association between carnitine metabolites in human plasma and sarcopenia in the discovery cohort
Plasma C5-CN levels were lower in men with sarcopenia than in those in the control group (P=0.005) (Table 3). C5-CN levels in men tended to be associated with HGS (P=0.098) and were significantly associated with the SMI (P=0.003) (Supplemental Table S3).
Increasing C5-CN levels per SD significantly decreased the odds of low muscle mass (OR, 0.61; 95% CI, 0.42 to 0.89) (Table 4) but not those of low muscle strength. According to the AUROC, the predictive ability of C5-CN levels for low muscle mass was 0.635 (95% CI, 0.544 to 0.7256; P=0.004) (Table 4). ROC curve analysis revealed that the optimal cutoff value for C5-CN levels, yielding the highest AUROC, was 0.33 pmol/μL.
Association between carnitine metabolites in human plasma and sarcopenia in the validation cohort
The main characteristics of the 68 participants in the validation cohort (21 cases and 47 age-matched controls) from the AMC are presented in Supplemental Table S4. Muscle mass parameters (lean mass, ASM, and SMI) and HGS of the case group were significantly lower than those of the control group (all, P<0.05). The sarcopenia group also had significantly lower C5-CN levels than the control group (P=0.012).
Association between carnitine metabolites in human muscle tissues and sarcopenia
The main characteristics of the 10 participants from whom human muscle tissue was retrieved in the validation cohort (five cases and 5 age-matched controls) from the AMC are presented in Supplemental Table S5. Muscle mass parameters (lean mass, ASM, and SMI), but not the HGS, of the case group were significantly lower than those of the control group (all, P<0.05). Muscle C12-CN levels were significantly higher in men with sarcopenia than in those in the control group (P=0.017) (Supplemental Table S6). Muscle C16-CN levels tended to be higher in men with sarcopenia than in those in the control group (P=0.083). Muscle C16-, C18-, and C18:1-CN levels were inversely correlated with the SMI. Muscle C12-CN levels tended to be inversely correlated with the SMI.
Predictive ability of C5-CN levels for sarcopenia in both the discovery and validation cohorts
C5-CN levels were lower in men with sarcopenia and associated with SMI. Therefore, we calculated the CN score using linear regression analysis of C5-CN levels with SMI in discovery cohort, defined by the formula: CN score=–0.006–[0.493×log (C5-CN)SD]. The corresponding ROC curve of the CN score had an AUROC of 0.635 (95% CI, 0.544 to 0.726) in the discovery cohort (Fig. 2). The AUROC did not significantly differ between the CN score and the indicator of low muscle strength (HGS <28 kg). Furthermore, addition of the CN score to low muscle strength as a predictor of sarcopenia significantly improved the AUROC by 12.6%, from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810, P=0.006; HGS+CN). In the validation cohort, the AUROC of the CN score was 0.692 (95% CI, 0.552 to 0.831). Despite the lack of statistical significance in the AUROC for low muscle strength (0.563; 95% CI, 0.470 to 0.656), addition of the CN score (AUROC, 0.712; 95% CI, 0.569 to 0.855; HGS+C5CN) substantially improved the AUROC by 26.4% (P=0.027) in the validation cohort.
In this study, the plasma levels of some CNs, including C5-CN, were lower in aged mice than in young mice. In addition, the levels of some short-chain CNs were positively correlated with muscle mass in mice. The plasma levels and muscle content of C5-CN in mice were positively associated with relative muscle mass. The levels of some CN metabolites in the cell lysate decreased during muscle cell differentiation. Furthermore, quantitation of CN metabolites from human plasma revealed that the plasma levels of C5-CN were lower in men with sarcopenia than in those without sarcopenia. Plasma C5-CN levels in men were associated with the SMI, which reflects muscle mass. A one SD increase in C5-CN levels reduced the odds of low muscle mass by 39%. The AUROC analysis revealed that the CN score, a model for predicting sarcopenia using plasma C5-CN levels, significantly predicted sarcopenia in men across two independent cohorts. Furthermore, addition of the CN score to HGS significantly improved the predictive performance of HGS for sarcopenia in the discovery cohort, based on a 12.6% increase, and in the validation cohort, based on a 26.4% increase according to the AUROC. To the best of our knowledge, this study is the first to identify the diagnostic potential of C5-CN for sarcopenia and its enhanced predictive accuracy when combined with HGS. Our findings indicate that C5-CN could serve as a clinical biomarker for diagnosing sarcopenia in men.
In the present study, the plasma C5-CN levels were lower in men with sarcopenia than in those without sarcopenia, indicating positive association of C5-CN with muscle mass. Furthermore, a significant association between low plasma C5-CN levels and sarcopenia was confirmed in two independent cohorts. These positive associations of C5-CN with muscle mass align with the results of previous studies [12-18]. Despite the lack of statistical significance (P=0.346 and P=0.084, respectively), the muscle C5-CN content was numerically lower in men with sarcopenia than in those without sarcopenia and tended to be positively associated with muscle mass. Interestingly, C5-CN levels in men were more strongly associated with muscle mass than with muscle strength, based on linear regression analysis. We could explain the association of C5-CN with muscle mass but not with muscle strength in the present study, which aligns with the results of previous studies [15,18]. Despite the ability of plasma C5-CN levels alone to predict sarcopenia, similar to HGS, the inclusion of plasma C5-CN levels alongside HGS, which reflects muscle strength, enhanced the predictive accuracy of HGS for sarcopenia in both the discovery and validation cohorts. These findings, if confirmed in another large independent cohort, might support the use of C5-CN as a biomarker for sarcopenia.
Consistent with the data derived from human studies, plasma C5-CN levels were lower in aged mice than in young mice and were inversely associated with muscle mass. Despite the lack of statistical significance (P=0.161), the muscle C5-CN content was numerically lower in aged mice than in young mice and was positively associated with muscle mass. As CN plays important roles in energy production and environmental conservation in the mitochondria of the skeletal muscle, CN insufficiency might induce loss of skeletal muscle [7-9]. In the present study, the decrease in the levels of some CN metabolites during muscle cell differentiation might be due to their utilization, as CN plays important roles in energy metabolism in the skeletal muscle. While it remains uncertain whether CN supplementation can improve physical performance in healthy individuals [9], these findings, if confirmed in patients with age-related sarcopenia, might support the use of C5-CN as a therapeutic target and biomarker for sarcopenia.
Besides the levels of C5-CN, a short-chain CN, the level of other plasma CNs was not found to be significantly associated with the parameters of sarcopenia. However, the muscle contents of some long-chain CNs were elevated in men with sarcopenia (C12, C16, and C18) and displayed an inverse correlation with the SMI (C16, C18, and C18:1), but not with HGS. Despite the small sample size used for the human muscle, our findings align with those of prior studies, which revealed an inverse association between the plasma levels of medium- and long-chain CNs and the SMI, gait speed, and physical performance [18-20]. We could not provide the exact mechanism for the differing associations between short-chain and medium- to long-chain CNs with muscle mass and strength. While C5-CN is a marker of mitochondrial function [7-9], medium- and long-chain CNs have been identified as markers of lipid-induced mitochondrial dysfunction in patients with type 2 diabetes and obesity [23]. This difference, attributed to chain length, may influence mitochondrial function and could explain the observed associations. Further studies are necessary to better understand the specific roles of short-chain versus medium- and long-chain CNs in sarcopenia.
Our study comprised a relatively large number of older men with matched controls; additionally, an independent validation cohort was used to assess the utility of CN as a biomarker for sarcopenia within a clinical context, highlighting a significant strength of our study. The animal and muscle cell experiments also strengthened the robustness and validity of our study findings. However, this study had some limitations. First, the causal relation between the identified metabolites and sarcopenia could not be inferred owing to the cross-sectional design of the study. Second, age-matched animal models of sarcopenia would be preferred instead of animals of different ages. Third, we cannot exclude the possibility of unmeasured confounding factors. The lack of dietary habit assessment limits a more thorough evaluation of the relationship between CN metabolites and sarcopenia. Fourth, the higher proportion of diabetes in the discovery cohort (86.1%) compared to the general population (29.8%) [24] may be due to the enrollment of participants from the Division of Endocrinology at the Veterans Health Service Medical Center. However, the proportion of diabetes was comparable between the control and sarcopenia groups.
In conclusion, our study demonstrates that C5-CN, which reflects muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies on CN metabolites are required to confirm these results and provide further insights into metabolomic changes relevant to the pathogenesis and diagnosis of sarcopenia.

Supplemental Table S1.

Baseline Characteristics of the Mouse Model according to the Status of Sarcopenia
enm-2024-2117-Supplemental-Table-S1.pdf

Supplemental Table S2.

Comparison of Muscular CN Contents (fmol/mg) between Young and Old Mice (Aging Mouse Model of Sarcopenia)
enm-2024-2117-Supplemental-Table-S2.pdf

Supplemental Table S3.

Association of C5-CN Levels with HGS and SMI of Men in the Discovery Cohort (n = 144): Linear Regression Analysis
enm-2024-2117-Supplemental-Table-S3.pdf

Supplemental Table S4.

Baseline Characteristics of Men in the Validation Cohort according to the Status of Sarcopenia (n = 68)
enm-2024-2117-Supplemental-Table-S4.pdf

Supplemental Table S5.

Baseline Characteristics of Men with Muscle Sample according to the Status of Sarcopenia (n = 10)
enm-2024-2117-Supplemental-Table-S5.pdf

Supplemental Table S6.

Comparison of Muscular CN Contents (fmol/mg) of Men with Muscle Sample between Control and Sarcopenia Groups and Correlation with SMI (n = 10)
enm-2024-2117-Supplemental-Table-S6.pdf

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: J.H.S., J.M.K., H.J.Y., S.H.L. Acquisition, analysis, or interpretation of data: J.H.S., J.M.K., H.J.C., H.K., Y.S.L., S.J.K., P.W.Y., W.K., S.J.B., H.K.K., H.J.Y., S.H.L. Drafting the work or revising: J.H.S., J.M.K., H.J.Y., S.H.L. Final approval of the manuscript: J.H.S., J.M.K., H.J.C., H.K., Y.S.L., S.J.K., P.W.Y., W.K., S.J.B., H.K.K., H.J.Y., S.H.L.

Acknowledgements
This study was funded by the Asan Institute for Life Sciences Grant (grant number: 2023IP0041), the Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2021-DD120859), and the National Research Foundation of Korea grant, funded by the Korean government (Ministry of Science and ICT; grant numbers: 2022R1C1C1002929, 2022R 1A2C1007901, and 2022R1A2C1003661).
Fig. 1.
Changes in carnitine (CN) levels during myoblast differentiation. CN levels in the cell lysates of myoblasts (MBs), myocytes (MCs), and myotubes (MTs). The error bar represents the standard deviation. P values were calculated using Mann-Whitney U test. Significant changes in the levels of each fatty acid amide in MCs and MTs compared to those in MBs are indicated by afor P<0.05 and bfor P<0.01.
enm-2024-2117f1.jpg
Fig. 2.
Receiver operating characteristic (ROC) curve of the carnitine (CN) score to detect sarcopenia in men in the (A) discovery cohort (n=144) and (B) validation cohort (n=68). CN score=–0.006–[0.493×log (C5-CN)SD]. SD, standard deviation; HGS, hand grip strength; AUROC, area under the receiver operating characteristic curve; CI, confidence interval.
enm-2024-2117f2.jpg
Table 1.
Comparison of Plasma CN Levels (fmol/μL) between Young and Old Mice (Aging Mouse Model of Sarcopenia) and Correlation with Relative Muscle Mas
Young mice (n=10) Old mice (n=7) P valuea P valueb r P valuec
C0-CN 15.40±7.73 18.30±13.53 0.581 0.635 0.049 0.852
C2-CN 68.67±19.80 40.74±18.04 0.010d 0.064 0.676d 0.003d
C3-CN 0.71±0.23 0.44±0.27 0.043d 0.094 0.585d 0.014d
C4-CN 0.59 (0.48–0.59) 0.44 (0.26–0.47) 0.015d 0.048d 0.575d 0.016d
C5-CN 0.28 (0.22–0.33) 0.16 (0.14–0.20) 0.004d 0.048d 0.619d 0.008d
C6-CN 0.09 (0.08–0.10) 0.06 (0.03–0.07) 0.017d 0.048d 0.493d 0.044d
C8-CN 0.02 (0.02–0.02) 0.01 (0.01–0.02) 0.040d 0.087 0.464 0.061
C10-CN 0.04±0.01 0.03±0.01 0.586 0.635 0.261 0.311
C12-CN 0.05±0.01 0.05±0.01 0.371 0.483 0.322 0.208
C14-CN 0.13 (0.12–0.14) 0.12 (0.11–0.15) 0.813 0.880 –0.059 0.824
C16-CN 0.38±0.07 0.29±0.07 0.013d 0.064 0.324 0.205
C18-CN 0.03±0.01 0.03±0.01 0.305 0.299 0.115 0.660
C18:1-CN 0.29±0.05 0.25±0.05 0.184 0.441 0.341 0.181

Values are expressed as mean±standard deviation or median (interquartile range).

CN, carnitine.

a P value by Student’s t test or Mann-Whitney U test;

b P value by Student’s t test or Mann-Whitney U test after adjusting for multiple testing corrections using the false discovery rate method;

c P value by Pearson correlation analysis or Spearman’s correlation analysis for CN levels with relative muscle mass;

d Statistically significant values.

Table 2.
Baseline Characteristics of Men in the Discovery Cohort according to the Status of Sarcopenia (n=144)
Disease Control (n=72) Sarcopenia (n=72) P value
Age, yr 74.0 (72.0–76.0) 74.0 (72.0–76.0) 0.989
Weight, kg 73.7±9.4a 55.7±5.9a <0.001a
Height, cm 167.8±4.8a 163.0±5.1a <0.001a
BMI, kg/m2 26.1 (24.1–27.9)a 21.1 (19.4–22.6)a <0.001a
Smoking 0.002a
 Ex-smoker 57 (79.2)a 42 (58.3)a
 Non-smoker 12 (16.7)a 13 (18.1)a
 Current smoker 3 (4.2)a 17 (23.6)a
Drinking 0.174
 No alcohol 34 (47.2) 41 (56.9)
 Alcohol <1/week 20 (27.8) 19 (26.4)
 Alcohol 1‒2/week 12 (16.7) 4 (5.6)
 Alcohol ≥3/week 6 (8.3) 8 (11.1)
Exercise 0.397
 No exercise 6 (8.3) 12 (16.7)
 Exercise <1/week 4 (5.6) 6 (8.3)
 Exercise 1‒2/week 12 (16.7) 10 (13.9)
 Exercise ≥3/week 50 (69.4) 44 (61.1)
Hypertension 50 (69.4) 37 (52.1) 0.051
Diabetes 60 (95.8) 64 (90.1) 0.314
FM, kg 21.6 (16.9–23.9)a 14.1 (11.2–17.8)a <0.001a
pFM, % 28.1±6.2a 25.0±6.6a 0.003a
EQ-VAS 75.0 (60.0–85.0)a 65.0 (50.0–77.5)a <0.001a
SARC-F 0.0 (0.0–1.0)a 1.0 (0.0–2.0)a 0.005a
HGS, kg 34.6±7.0a 28.5±5.6a <0.001a
Chair stand up test, sec 7.0 (6.0;9.0) 7.0 (5.0;10.0) 0.874
LM, kg 50.0±4.2a 39.4±2.7a <0.001a
ASM, kg 22.6±2.2a 17.1±1.5a <0.001a
SMI, kg/m2 8.0 (7.6–8.4)a 6.5 (6.2–6.6)a <0.001a

Values are expressed as median (interquartile range), mean±standard deviation, or number (%). P value by Student’s t test or Mann-Whitney U test for continuous variables or by chi-square or Fisher’s exact test for categorical variables.

BMI, body mass index; FM, fat mass; pFM, percent fat mass; EQ-VAS, EuroQol Visual Analogue Scale; SARC-F, Strength, Ambulation, Rising from a chair, stair Climbing, and history of Falling; HGS, hand grip strength; LM, lean mass; ASM, appendicular skeletal muscle mass; SMI, skeletal muscle mass index.

a Statistically significant values.

Table 3.
Comparison of Plasma CN Levels (pmol/μL) of Men between Control and Sarcopenia Groups in the Discovery Cohort (n=144)
Control (n=72) Case (n=72) Log2 (FC) P valuea P valueb
C0-CN 78.02 (67.47–90.56) 73.17 (59.26–89.36) –0.083 0.131 0.851
C2-CN 33.63 (28.27–40.03) 33.75 (26.64–44.27) 0.075 0.848 0.939
C3-CN 2.29 (1.96–2.84) 2.29 (1.71–2.61) –0.130 0.242 0.939
C4-CN 0.89 (0.73–1.15) 0.90 (0.69–1.19) 0.012 0.870 0.939
C5-CN 0.41 (0.34–0.52)c 0.35 (0.26–0.46)c –0.308c 0.005c 0.068
C6-CN 0.19 (0.15–0.25) 0.19 (0.12–0.27) 0.185 0.694 0.939
C8-CN 0.47 (0.29–0.73) 0.41 (0.27–0.78) 0.189 0.643 0.939
C10-0CN 0.68 (0.51–0.94) 0.68 (0.46–1.06) 0.261 0.939 0.939
C12-CN 0.18 (0.14–0.23) 0.18 (0.10–0.29) 0.313 0.917 0.939
C14-CN 0.04 (0.03–0.05) 0.04 (0.03–0.06) 0.310 0.607 0.939
C16-CN 0.11 (0.10–0.13) 0.11 (0.08–0.13) –0.002 0.632 0.939
C18-CN 0.03 (0.02–0.03) 0.03 (0.02–0.03) 0.045 0.487 0.939
C18:1-CN 0.26 (0.21–0.38) 0.27 (0.21–0.36) 0.041 0.745 0.939

Values are expressed as median (interquartile range).

CN, carnitine; FC, fold change.

a P value by Mann-Whitney U test;

b P value by Mann-Whitney U test after adjusting for multiple testing corrections using the false discovery rate method;

c Statistically significant values.

Table 4.
Association of C5 CN Level (pmol/μL) with Low Muscle Strength and Low Muscle Mass of Men in the Discovery Cohort (n=144): Logistic Regression Analysis and ROC Analysis
OR (95% CI) P value AUROC (95% CI) P value Cutoff
Low muscle strength
 C5-CN per 1 SD 0.83 (0.57–1.21) 0.337 0.461 (0.356–0.567) 0.472
 C5-CN per 1 log 0.35 (0.04–2.95) 0.337 0.461 (0.356–0.567) 0.472 0.38
Low muscle mass
 C5-CN per 1 SD 0.61 (0.42–0.89)a 0.010a 0.635 (0.544–0.726)a 0.004a
 C5-CN per 1 log 0.06 (0.01–0.52)a 0.010a 0.635 (0.544–0.726)a 0.004a 0.33a

C5-CN levels were log-transformed due to their skewed distribution. Cutoff point of hand grip strength for low muscle strength was <28 kg. Cutoff point of SMI for low muscle mass was <7.0 kg/m2.

CN, carnitine; ROC, receiver operating characteristic; OR, odds ratio; CI, confidence interval; AUROC, area under the receiver operating characteristic curve; SD, standard deviation.

a Statistically significant values.

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Figure & Data

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      Carnitine Metabolite as a Potential Circulating Biomarker for Sarcopenia in Men
      Image Image
      Fig. 1. Changes in carnitine (CN) levels during myoblast differentiation. CN levels in the cell lysates of myoblasts (MBs), myocytes (MCs), and myotubes (MTs). The error bar represents the standard deviation. P values were calculated using Mann-Whitney U test. Significant changes in the levels of each fatty acid amide in MCs and MTs compared to those in MBs are indicated by afor P<0.05 and bfor P<0.01.
      Fig. 2. Receiver operating characteristic (ROC) curve of the carnitine (CN) score to detect sarcopenia in men in the (A) discovery cohort (n=144) and (B) validation cohort (n=68). CN score=–0.006–[0.493×log (C5-CN)SD]. SD, standard deviation; HGS, hand grip strength; AUROC, area under the receiver operating characteristic curve; CI, confidence interval.

      Fig. 1.

      Fig. 2.

      Carnitine Metabolite as a Potential Circulating Biomarker for Sarcopenia in Men
      Young mice (n=10) Old mice (n=7) P valuea P valueb r P valuec
      C0-CN 15.40±7.73 18.30±13.53 0.581 0.635 0.049 0.852
      C2-CN 68.67±19.80 40.74±18.04 0.010d 0.064 0.676d 0.003d
      C3-CN 0.71±0.23 0.44±0.27 0.043d 0.094 0.585d 0.014d
      C4-CN 0.59 (0.48–0.59) 0.44 (0.26–0.47) 0.015d 0.048d 0.575d 0.016d
      C5-CN 0.28 (0.22–0.33) 0.16 (0.14–0.20) 0.004d 0.048d 0.619d 0.008d
      C6-CN 0.09 (0.08–0.10) 0.06 (0.03–0.07) 0.017d 0.048d 0.493d 0.044d
      C8-CN 0.02 (0.02–0.02) 0.01 (0.01–0.02) 0.040d 0.087 0.464 0.061
      C10-CN 0.04±0.01 0.03±0.01 0.586 0.635 0.261 0.311
      C12-CN 0.05±0.01 0.05±0.01 0.371 0.483 0.322 0.208
      C14-CN 0.13 (0.12–0.14) 0.12 (0.11–0.15) 0.813 0.880 –0.059 0.824
      C16-CN 0.38±0.07 0.29±0.07 0.013d 0.064 0.324 0.205
      C18-CN 0.03±0.01 0.03±0.01 0.305 0.299 0.115 0.660
      C18:1-CN 0.29±0.05 0.25±0.05 0.184 0.441 0.341 0.181
      Disease Control (n=72) Sarcopenia (n=72) P value
      Age, yr 74.0 (72.0–76.0) 74.0 (72.0–76.0) 0.989
      Weight, kg 73.7±9.4a 55.7±5.9a <0.001a
      Height, cm 167.8±4.8a 163.0±5.1a <0.001a
      BMI, kg/m2 26.1 (24.1–27.9)a 21.1 (19.4–22.6)a <0.001a
      Smoking 0.002a
       Ex-smoker 57 (79.2)a 42 (58.3)a
       Non-smoker 12 (16.7)a 13 (18.1)a
       Current smoker 3 (4.2)a 17 (23.6)a
      Drinking 0.174
       No alcohol 34 (47.2) 41 (56.9)
       Alcohol <1/week 20 (27.8) 19 (26.4)
       Alcohol 1‒2/week 12 (16.7) 4 (5.6)
       Alcohol ≥3/week 6 (8.3) 8 (11.1)
      Exercise 0.397
       No exercise 6 (8.3) 12 (16.7)
       Exercise <1/week 4 (5.6) 6 (8.3)
       Exercise 1‒2/week 12 (16.7) 10 (13.9)
       Exercise ≥3/week 50 (69.4) 44 (61.1)
      Hypertension 50 (69.4) 37 (52.1) 0.051
      Diabetes 60 (95.8) 64 (90.1) 0.314
      FM, kg 21.6 (16.9–23.9)a 14.1 (11.2–17.8)a <0.001a
      pFM, % 28.1±6.2a 25.0±6.6a 0.003a
      EQ-VAS 75.0 (60.0–85.0)a 65.0 (50.0–77.5)a <0.001a
      SARC-F 0.0 (0.0–1.0)a 1.0 (0.0–2.0)a 0.005a
      HGS, kg 34.6±7.0a 28.5±5.6a <0.001a
      Chair stand up test, sec 7.0 (6.0;9.0) 7.0 (5.0;10.0) 0.874
      LM, kg 50.0±4.2a 39.4±2.7a <0.001a
      ASM, kg 22.6±2.2a 17.1±1.5a <0.001a
      SMI, kg/m2 8.0 (7.6–8.4)a 6.5 (6.2–6.6)a <0.001a
      Control (n=72) Case (n=72) Log2 (FC) P valuea P valueb
      C0-CN 78.02 (67.47–90.56) 73.17 (59.26–89.36) –0.083 0.131 0.851
      C2-CN 33.63 (28.27–40.03) 33.75 (26.64–44.27) 0.075 0.848 0.939
      C3-CN 2.29 (1.96–2.84) 2.29 (1.71–2.61) –0.130 0.242 0.939
      C4-CN 0.89 (0.73–1.15) 0.90 (0.69–1.19) 0.012 0.870 0.939
      C5-CN 0.41 (0.34–0.52)c 0.35 (0.26–0.46)c –0.308c 0.005c 0.068
      C6-CN 0.19 (0.15–0.25) 0.19 (0.12–0.27) 0.185 0.694 0.939
      C8-CN 0.47 (0.29–0.73) 0.41 (0.27–0.78) 0.189 0.643 0.939
      C10-0CN 0.68 (0.51–0.94) 0.68 (0.46–1.06) 0.261 0.939 0.939
      C12-CN 0.18 (0.14–0.23) 0.18 (0.10–0.29) 0.313 0.917 0.939
      C14-CN 0.04 (0.03–0.05) 0.04 (0.03–0.06) 0.310 0.607 0.939
      C16-CN 0.11 (0.10–0.13) 0.11 (0.08–0.13) –0.002 0.632 0.939
      C18-CN 0.03 (0.02–0.03) 0.03 (0.02–0.03) 0.045 0.487 0.939
      C18:1-CN 0.26 (0.21–0.38) 0.27 (0.21–0.36) 0.041 0.745 0.939
      OR (95% CI) P value AUROC (95% CI) P value Cutoff
      Low muscle strength
       C5-CN per 1 SD 0.83 (0.57–1.21) 0.337 0.461 (0.356–0.567) 0.472
       C5-CN per 1 log 0.35 (0.04–2.95) 0.337 0.461 (0.356–0.567) 0.472 0.38
      Low muscle mass
       C5-CN per 1 SD 0.61 (0.42–0.89)a 0.010a 0.635 (0.544–0.726)a 0.004a
       C5-CN per 1 log 0.06 (0.01–0.52)a 0.010a 0.635 (0.544–0.726)a 0.004a 0.33a
      Table 1. Comparison of Plasma CN Levels (fmol/μL) between Young and Old Mice (Aging Mouse Model of Sarcopenia) and Correlation with Relative Muscle Mas

      Values are expressed as mean±standard deviation or median (interquartile range).

      CN, carnitine.

      P value by Student’s t test or Mann-Whitney U test;

      P value by Student’s t test or Mann-Whitney U test after adjusting for multiple testing corrections using the false discovery rate method;

      P value by Pearson correlation analysis or Spearman’s correlation analysis for CN levels with relative muscle mass;

      Statistically significant values.

      Table 2. Baseline Characteristics of Men in the Discovery Cohort according to the Status of Sarcopenia (n=144)

      Values are expressed as median (interquartile range), mean±standard deviation, or number (%). P value by Student’s t test or Mann-Whitney U test for continuous variables or by chi-square or Fisher’s exact test for categorical variables.

      BMI, body mass index; FM, fat mass; pFM, percent fat mass; EQ-VAS, EuroQol Visual Analogue Scale; SARC-F, Strength, Ambulation, Rising from a chair, stair Climbing, and history of Falling; HGS, hand grip strength; LM, lean mass; ASM, appendicular skeletal muscle mass; SMI, skeletal muscle mass index.

      Statistically significant values.

      Table 3. Comparison of Plasma CN Levels (pmol/μL) of Men between Control and Sarcopenia Groups in the Discovery Cohort (n=144)

      Values are expressed as median (interquartile range).

      CN, carnitine; FC, fold change.

      P value by Mann-Whitney U test;

      P value by Mann-Whitney U test after adjusting for multiple testing corrections using the false discovery rate method;

      Statistically significant values.

      Table 4. Association of C5 CN Level (pmol/μL) with Low Muscle Strength and Low Muscle Mass of Men in the Discovery Cohort (n=144): Logistic Regression Analysis and ROC Analysis

      C5-CN levels were log-transformed due to their skewed distribution. Cutoff point of hand grip strength for low muscle strength was <28 kg. Cutoff point of SMI for low muscle mass was <7.0 kg/m2.

      CN, carnitine; ROC, receiver operating characteristic; OR, odds ratio; CI, confidence interval; AUROC, area under the receiver operating characteristic curve; SD, standard deviation.

      Statistically significant values.

      Table 1.

      Table 2.

      Table 3.

      Table 4.

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