{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:18:18Z","timestamp":1785421098517,"version":"3.56.0"},"reference-count":76,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371185"],"award-info":[{"award-number":["32371185"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32371185"],"award-info":[{"award-number":["32371185"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Shanghai Oriental Talents Program"},{"name":"Shanghai Science and Technology Plan Project","award":["23010504200"],"award-info":[{"award-number":["23010504200"]}]},{"name":"Key Lab of Exercise and Health Sciences of Ministry of Education","award":["2025KF002"],"award-info":[{"award-number":["2025KF002"]}]},{"award":["2025KF002"],"award-info":[{"award-number":["2025KF002"]}],"id":[{"id":"https:\/\/ror.org\/0056pyw12","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Shanghai Key Lab of Human Performance","award":["11DZ2261100"],"award-info":[{"award-number":["11DZ2261100"]}]},{"award":["11DZ2261100"],"award-info":[{"award-number":["11DZ2261100"]}],"id":[{"id":"https:\/\/ror.org\/0056pyw12","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Objective: Impaired fatty acid oxidation (FAO) is considered an important metabolic mechanism underlying skeletal muscle aging and sarcopenia; however, the key regulatory molecules involved in this process remain incompletely defined. This study aimed to identify candidate biomarkers associated with impaired FAO in aged skeletal muscle, characterize their potential biological functions and regulatory features through integrated bioinformatics and machine learning analyses, and preliminarily validate their expression patterns in in vivo and in vitro aging models. Methods: Skeletal muscle aging transcriptomic datasets GSE1428 and GSE674 were obtained from the Gene Expression Omnibus database. FAO-related genes were retrieved from GeneCards. Differentially expressed FAO-related genes (DE-FAOGs) were identified through differential expression analysis and were further analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Random forest, Boruta, and protein\u2013protein interaction (PPI) network analyses were used to screen hub genes, and an artificial neural network (ANN) model was constructed. Single-cell RNA sequencing analysis, gene set enrichment analysis, ceRNA network construction, drug prediction, molecular docking, and molecular dynamics simulation were further performed. Hub gene expression was validated by qRT-PCR in naturally aged mice and D-galactose-induced senescent C2C12 cells. Results: A total of 69 DE-FAOGs were identified and were mainly enriched in mitochondrial function, electron transport chain, and energy metabolism-related pathways. Three hub genes, creatine kinase, mitochondrial 2 (CKMT2), actin alpha cardiac muscle 1 (ACTC1), and forkhead box O3 (FOXO3), were identified by random forest, Boruta, and PPI analyses. Receiver operating characteristic (ROC) analysis showed good discriminatory performance for these genes. The three-gene ANN model achieved area under the curve (AUC) values of 0.992 and 0.964 in the training and validation datasets, respectively. Gene set enrichment analysis (GSEA) suggested that the hub genes were closely associated with mitochondrial energy metabolism, lipid metabolism, and stress regulation. qRT-PCR confirmed decreased Ckmt2 expression and increased Actc1 and Foxo3 expression under aging conditions, consistent with the bioinformatics results. Conclusions: CKMT2, ACTC1, and FOXO3 are potential biomarkers associated with impaired FAO in aged skeletal muscle. The ANN model based on these three genes showed good predictive performance and may provide new insights into the metabolic mechanisms and therapeutic targets of sarcopenia.<\/jats:p>","DOI":"10.3390\/biom16071030","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:58Z","timestamp":1784077558000},"page":"1030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Potential Biomarkers Associated with Impaired Fatty Acid Oxidation in Aged Skeletal Muscle Using Bioinformatics and Machine Learning Approaches"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3773-8151","authenticated-orcid":false,"given":"Haoyang","family":"Gao","sequence":"first","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangjie","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabin","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Ji","sequence":"additional","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Ma","sequence":"additional","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danlin","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Humanities and Social Sciences, Shanghai Lida University, Shanghai 201609, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"},{"name":"School of Physical Education, Shanghai Normal University, Shanghai 200234, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Xiao","sequence":"additional","affiliation":[{"name":"Shanghai Key Lab of Human Performance, Shanghai University of Sport, 650 Qingyuan Ring Road, Yangpu District, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","unstructured":"GBD 2021 Forecasting Collaborators (2024). Burden of Disease Scenarios for 204 Countries and Territories, 2022\u20132050: A Forecasting Analysis for the Global Burden of Disease Study 2021. Lancet, 403, 2204\u20132256."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1038\/s43587-025-00999-8","article-title":"Adapting Health, Economic and Social Policies to Address Population Aging in China","volume":"5","author":"Fang","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41572-024-00550-w","article-title":"Sarcopenia","volume":"10","author":"Sayer","year":"2024","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155533","DOI":"10.1016\/j.metabol.2023.155533","article-title":"Epidemiology of Sarcopenia: Prevalence, Risk Factors, and Consequences","volume":"144","author":"Yuan","year":"2023","journal-title":"Metabolism"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1152\/physrev.00061.2017","article-title":"Sarcopenia: Aging-Related Loss of Muscle Mass and Function","volume":"99","author":"Larsson","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1007\/s12603-018-1139-9","article-title":"International Clinical Practice Guidelines for Sarcopenia (Icfsr): Screening, Diagnosis and Management","volume":"22","author":"Dent","year":"2018","journal-title":"J. Nutr. Health Aging"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41574-020-0405-1","article-title":"Tuning Fatty Acid Oxidation in Skeletal Muscle with Dietary Fat and Exercise","volume":"16","author":"Fritzen","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.bbrc.2005.12.011","article-title":"Ampk Activation Increases Fatty Acid Oxidation in Skeletal Muscle by Activating Pparalpha and Pgc-1","volume":"340","author":"Lee","year":"2006","journal-title":"Biochem Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12017","DOI":"10.1073\/pnas.0705070104","article-title":"Amp-Activated Protein Kinase (Ampk) Action in Skeletal Muscle Via Direct Phosphorylation of Pgc-1alpha","volume":"104","author":"Jager","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vieira-Lara, M.A., Dommerholt, M.B., Zhang, W., Blankestijn, M., Wolters, J.C., Abegaz, F., Gerding, A., van der Veen, Y.T., Thomas, R., and van Os, R.P. (2021). Age-Related Susceptibility to Insulin Resistance Arises from a Combination of Cpt1b Decline and Lipid Overload. BMC Biol., 19.","DOI":"10.1186\/s12915-021-01082-5"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/jcsm.12901","article-title":"Pathogenesis of Sarcopenia and the Relationship with Fat Mass: Descriptive Review","volume":"13","author":"Li","year":"2022","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.cmet.2012.04.010","article-title":"Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle","volume":"15","author":"Muoio","year":"2012","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s41586-024-07348-6","article-title":"Multimodal Cell Atlas of the Ageing Human Skeletal Muscle","volume":"629","author":"Lai","year":"2024","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.freeradbiomed.2024.08.018","article-title":"Oxidative Phosphorylation and Fatty Acid Oxidation in Slow-Aging Mice","volume":"224","author":"Elmansi","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhu, D., Wang, L., Gao, H., Wang, Z., Li, K., Ma, X., Zhao, L., and Xiao, W. (2025). Aerobic Exercise Delays Age-Related Sarcopenia in Mice Via Alleviating Imbalance in Mitochondrial Quality Control. Metabolites, 15.","DOI":"10.3390\/metabo15070472"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D138","DOI":"10.1093\/nar\/gkad965","article-title":"Ncbi Geo: Archive for Gene Expression and Epigenomics Data Sets: 23-Year Update","volume":"52","author":"Clough","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101576","DOI":"10.1016\/j.arr.2022.101576","article-title":"Multi-Omics Research in Sarcopenia: Current Progress and Future Prospects","volume":"76","author":"Liu","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1002\/jcsm.13562","article-title":"Artificial Neural Network Inference Analysis Identified Novel Genes and Gene Interactions Associated with Skeletal Muscle Aging","volume":"15","author":"Tarum","year":"2024","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.neuron.2018.08.011","article-title":"Molecular Dynamics Simulation for All","volume":"99","author":"Hollingsworth","year":"2018","journal-title":"Neuron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/ajcn\/50.5.1231","article-title":"Summary Comments","volume":"50","author":"Rosenberg","year":"1989","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/ageing\/afy169","article-title":"Sarcopenia: Revised European Consensus on Definition and Diagnosis","volume":"48","author":"Bahat","year":"2019","journal-title":"Age Ageing"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, X., Zhang, W., Wang, C., Tao, W., Dou, Q., and Yang, Y. (2018). Sarcopenia as a Predictor of Hospitalization among Older People: A Systematic Review and Meta-Analysis. BMC Geriatr., 18.","DOI":"10.1186\/s12877-018-0878-0"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/jcsm.12411","article-title":"Sarcopenia and Its Association with Falls and Fractures in Older Adults: A Systematic Review and Meta-Analysis","volume":"10","author":"Yeung","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1016\/j.afos.2021.02.001","article-title":"Sarcopenia and Mortality in Different Clinical Conditions: A Meta-Analysis","volume":"7","author":"Lee","year":"2021","journal-title":"Osteoporos. Sarcopenia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s41574-021-00626-7","article-title":"Mitochondrial and Metabolic Dysfunction in Ageing and Age-Related Diseases","volume":"18","author":"Amorim","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The Hallmarks of Aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s12944-025-02622-6","article-title":"Targeting Intramyocellular Lipids to Improve Aging Muscle Function","volume":"24","author":"Russ","year":"2025","journal-title":"Lipids Health Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1007\/s11357-022-00567-7","article-title":"Obesity as a Premature Aging Phenotype\u2014Implications for Sarcopenic Obesity","volume":"44","author":"Nunan","year":"2022","journal-title":"Geroscience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1146\/annurev-physiol-020518-114310","article-title":"Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging","volume":"81","author":"Hood","year":"2019","journal-title":"Annu Rev. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/gerona\/gly113","article-title":"Peroxiredoxin2 Deficiency Aggravates Aging-Induced Insulin Resistance and Declines Muscle Strength","volume":"74","author":"Cha","year":"2019","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5808","DOI":"10.1038\/s41467-019-13694-1","article-title":"Mitochondrial Oxidative Capacity and Nad(+) Biosynthesis Are Reduced in Human Sarcopenia across Ethnicities","volume":"10","author":"Migliavacca","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5618","DOI":"10.1073\/pnas.0501559102","article-title":"Decline in Skeletal Muscle Mitochondrial Function with Aging in Humans","volume":"102","author":"Short","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/j.1474-9726.2012.00844.x","article-title":"The Impact of Aging on Mitochondrial Function and Biogenesis Pathways in Skeletal Muscle of Sedentary High- and Low-Functioning Elderly Individuals","volume":"11","author":"Joseph","year":"2012","journal-title":"Aging Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13105-024-01062-7","article-title":"The Link between Mitochondria and Sarcopenia","volume":"81","author":"Kamarulzaman","year":"2025","journal-title":"J. Physiol. Biochem"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lu, Y., Li, T., Shu, Y., Lu, C., Luo, Z., Wang, J., Xiong, H., and Li, W. (2025). Lipid Peroxidation and Sarcopenia: Molecular Mechanisms and Potential Therapeutic Approaches. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1525205"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1007\/s40279-024-02007-2","article-title":"Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle","volume":"54","author":"Reisman","year":"2024","journal-title":"Sports Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/s41422-018-0078-7","article-title":"Skeletal Muscle Mitochondrial Remodeling in Exercise and Diseases","volume":"28","author":"Gan","year":"2018","journal-title":"Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e1800404","DOI":"10.1002\/pmic.201800404","article-title":"Mitochondrial Dysfunction in Age-Related Metabolic Disorders","volume":"20","author":"Natarajan","year":"2020","journal-title":"Proteomics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6937","DOI":"10.1074\/jbc.275.10.6937","article-title":"Direct Evidence for the Control of Mitochondrial Respiration by Mitochondrial Creatine Kinase in Oxidative Muscle Cells in Situ","volume":"275","author":"Kay","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"eado3022","DOI":"10.1126\/scitranslmed.ado3022","article-title":"Decreased Mitochondrial Creatine Kinase 2 Impairs Skeletal Muscle Mitochondrial Function Independently of Insulin in Type 2 Diabetes","volume":"16","author":"Guimaraes","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e70542","DOI":"10.1096\/fj.202500375R","article-title":"Nor-1 Overexpression Elevates Myoglobin Expression Via Perm1 and Enhances Mitochondrial Function and Endurance in Skeletal Muscles of Aged Mice","volume":"39","author":"Paez","year":"2025","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lang, A., Oehler, D., Benkhoff, M., Reinders, Y., Barcik, M., Shahrjerdi, K., Kaldirim, M., Sickmann, A., Dannenberg, L., and Polzin, A. (2024). Mitochondrial Creatine Kinase 2 (Ckmt2) as a Plasma-Based Biomarker for Evaluating Reperfusion Injury in Acute Myocardial Infarction. Biomedicines, 12.","DOI":"10.3390\/biomedicines12102368"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.bbagrm.2017.08.004","article-title":"Variable Cardiac Alpha-Actin (Actc1) Expression in Early Adult Skeletal Muscle Correlates with Promoter Methylation","volume":"1860","author":"Boutilier","year":"2017","journal-title":"Biochim Biophys. Acta Gene Regul. Mech."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1038\/s41556-023-01271-0","article-title":"Regenerating Human Skeletal Muscle Forms an Emerging Niche in Vivo to Support Pax7 Cells","volume":"25","author":"Hicks","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_45","first-page":"1985","article-title":"Alpha-Skeletal and Alpha-Cardiac Actin Genes Are Coexpressed in Adult Human Skeletal Muscle and Heart","volume":"3","author":"Gunning","year":"1983","journal-title":"Mol. Cell. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2024070005","DOI":"10.1542\/peds.2024-070005","article-title":"Neonatal Cardiac Dilation and Dysfunction: Time to Look in the Genes","volume":"155","author":"Rousset","year":"2025","journal-title":"Pediatrics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1006\/jmcc.2000.1204","article-title":"Inherited and De Novo Mutations in the Cardiac Actin Gene Cause Hypertrophic Cardiomyopathy","volume":"32","author":"Olson","year":"2000","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"121877","DOI":"10.1016\/j.lfs.2023.121877","article-title":"The Rules and Regulatory Mechanisms of Foxo3 on Inflammation, Metabolism, Cell Death and Aging in Hosts","volume":"328","author":"Cao","year":"2023","journal-title":"Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrm3507","article-title":"Foxos: Signalling Integrators for Homeostasis Maintenance","volume":"14","author":"Eijkelenboom","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1080\/15548627.2023.2288528","article-title":"Carm1 Drives Mitophagy and Autophagy Flux During Fasting-Induced Skeletal Muscle Atrophy","volume":"20","author":"Stouth","year":"2024","journal-title":"Autophagy"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0092-8674(04)00400-3","article-title":"Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy","volume":"117","author":"Sandri","year":"2004","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2007.11.004","article-title":"Foxo3 Coordinately Activates Protein Degradation by the Autophagic\/Lysosomal and Proteasomal Pathways in Atrophying Muscle Cells","volume":"6","author":"Zhao","year":"2007","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.1038\/ncomms7670","article-title":"Regulation of Autophagy and the Ubiquitin-Proteasome System by the Foxo Transcriptional Network During Muscle Atrophy","volume":"6","author":"Milan","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s00018-025-05756-z","article-title":"Mitochondrial Oxidative Stress Inhibited Sirt3\/Foxo3\/Pparalpha Pathway and Aggravated Copper and Zinc Co-Deficiency-Induced Hepatic Lipotoxicity in a Fish Model","volume":"82","author":"Zhong","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/nrc2223","article-title":"The Emerging Roles of Forkhead Box (Fox) Proteins in Cancer","volume":"7","author":"Myatt","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3892\/mmr.2022.12921","article-title":"Foxo3 Is a Potential Biomarker and Therapeutic Target for Premature Ovarian Insufficiency (Review)","volume":"27","author":"Meng","year":"2023","journal-title":"Mol. Med. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2423759","DOI":"10.1080\/08916934.2024.2423759","article-title":"Foxo3 as a Potential Diagnostic Biomarker for Autophagy in Rheumatoid Arthritis: A Bioinformatics Study","volume":"57","author":"Deng","year":"2024","journal-title":"Autoimmunity"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.cmet.2009.12.009","article-title":"Foxo-Mediated Defense against Oxidative Stress in Osteoblasts Is Indispensable for Skeletal Homeostasis in Mice","volume":"11","author":"Ambrogini","year":"2010","journal-title":"Cell Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1007\/s00198-017-4151-8","article-title":"Osteosarcopenia: Where Bone, Muscle, and Fat Collide","volume":"28","author":"Hirschfeld","year":"2017","journal-title":"Osteoporos. Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"18156","DOI":"10.1038\/s41598-024-69284-9","article-title":"A Comprehensive Single-Cell Rna Transcriptomic Analysis Identifies a Unique Spp1+ Macrophages Subgroup in Aging Skeletal Muscle","volume":"14","author":"Bi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"C1098","DOI":"10.1152\/ajpcell.00171.2013","article-title":"Type-1 Pericytes Participate in Fibrous Tissue Deposition in Aged Skeletal Muscle","volume":"305","author":"Birbrair","year":"2013","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00441-023-03816-z","article-title":"The Benefits and Pitfalls of Machine Learning for Biomarker Discovery","volume":"394","author":"Ng","year":"2023","journal-title":"Cell Tissue Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"107739","DOI":"10.1016\/j.biotechadv.2021.107739","article-title":"Using Machine Learning Approaches for Multi-Omics Data Analysis: A Review","volume":"49","author":"Reel","year":"2021","journal-title":"Biotechnol. Adv."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cell.2011.07.014","article-title":"A Cerna Hypothesis: The Rosetta Stone of a Hidden Rna Language?","volume":"146","author":"Salmena","year":"2011","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.cell.2011.09.028","article-title":"A Long Noncoding Rna Controls Muscle Differentiation by Functioning as a Competing Endogenous Rna","volume":"147","author":"Cesana","year":"2011","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1038\/mt.2012.35","article-title":"Loss of Mir-29 in Myoblasts Contributes to Dystrophic Muscle Pathogenesis","volume":"20","author":"Wang","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"155117","DOI":"10.1016\/j.phymed.2023.155117","article-title":"Isovitexin Alleviates Hepatic Fibrosis by Regulating Mir-21-Mediated Pi3k\/Akt Signaling and Glutathione Metabolic Pathway: Based on Transcriptomics and Metabolomics","volume":"121","author":"Huang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e33062","DOI":"10.1016\/j.heliyon.2024.e33062","article-title":"Mir-21 Regulates Skeletal Muscle Atrophy and Fibrosis by Targeting Tgf-Beta\/Smad7-Smad2\/3 Signaling Pathway","volume":"10","author":"Song","year":"2024","journal-title":"Heliyon"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ebiom.2016.01.035","article-title":"Mir-378 Activates the Pyruvate-Pep Futile Cycle and Enhances Lipolysis to Ameliorate Obesity in Mice","volume":"5","author":"Zhang","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nature12986","article-title":"The Multilayered Complexity of Cerna Crosstalk and Competition","volume":"505","author":"Tay","year":"2014","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13321-020-00450-7","article-title":"A Review of Computational Drug Repositioning: Strategies, Approaches, Opportunities, Challenges, and Directions","volume":"12","author":"Jarada","year":"2020","journal-title":"J. Cheminform"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1146\/annurev-biodatasci-110123-025333","article-title":"Computational Approaches to Drug Repurposing: Methods, Challenges, and Opportunities","volume":"7","author":"Cousins","year":"2024","journal-title":"Annu Rev. BioMed Data Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.molcel.2017.09.034","article-title":"Cdk4 Phosphorylates Ampkalpha2 to Inhibit Its Activity and Repress Fatty Acid Oxidation","volume":"68","author":"Lagarrigue","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"C995","DOI":"10.1152\/ajpcell.00520.2010","article-title":"Glycogen Synthase Kinase-3beta Is Required for the Induction of Skeletal Muscle Atrophy","volume":"301","author":"Verhees","year":"2011","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"bqz046","DOI":"10.1210\/endocr\/bqz046","article-title":"Cpt1a-Mediated Fat Oxidation, Mechanisms, and Therapeutic Potential","volume":"161","author":"Schlaepfer","year":"2020","journal-title":"Endocrinology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S1097-2765(04)00211-4","article-title":"The Igf-1\/Pi3k\/Akt Pathway Prevents Expression of Muscle Atrophy-Induced Ubiquitin Ligases by Inhibiting Foxo Transcription Factors","volume":"14","author":"Stitt","year":"2004","journal-title":"Mol. 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