{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:07:16Z","timestamp":1792789636433,"version":"4.5.0"},"reference-count":102,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gyeongsang National University","id":[{"id":"https:\/\/ror.org\/00saywf64","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00saywf64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Sarcopenia is a progressive and generalized skeletal muscle disorder characterized primarily by reduced muscle strength, with low muscle quantity or quality confirming the diagnosis and poor physical performance indicating greater severity. Although human studies and animal models remain essential, their use is constrained by ethical considerations, inter-individual variability, species-specific differences, cost, and the difficulty of isolating individual mechanisms within whole-body systems. This review critically evaluates in vitro models that reproduce selected sarcopenia-related pathological phenotypes, experimental approaches for studying exercise-associated adaptations, and in silico methods for translational benchmarking. We compare myogenic cell cultures, three-dimensional engineered muscle tissues, senescence-inducing systems, and microphysiological platforms according to the phenotypes modeled, principal endpoints, strengths, and limitations. We then assess electrical pulse stimulation, mechanical stretch, and pathway-targeted pharmacological probes as reductionist tools for examining contraction-associated, load-sensitive, humoral, and metabolic responses rather than reproducing whole-body exercise. Finally, we discuss how multi-omics profiling, machine learning, deep learning, public transcriptomic datasets, and cell-type-aware analyses can benchmark in vitro signatures against in vivo data while accounting for batch effects, dataset heterogeneity, cell-composition confounding, overfitting, interpretability, and external validation. Integrating experimentally validated findings with clearly identified hypothesis-generating observations may improve model selection, reduce reliance on animal experiments where appropriate, and accelerate the development of interventions to preserve skeletal muscle function during aging.<\/jats:p>","DOI":"10.3390\/ijms27198609","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8609","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Modeling of Sarcopenia-Related Pathology and Exercise-Associated Adaptations: Integration with In Silico Approaches"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8445-3773","authenticated-orcid":false,"given":"Kyung-Wan","family":"Baek","sequence":"first","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea"},{"name":"Department of Physical Education, Gyeongsang National University, Jinju 52828, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Ri","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Gyeongsang National University, Jinju 52828, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea"},{"name":"Department of Physical Education, Gyeongsang National University, Jinju 52828, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3489-7798","authenticated-orcid":false,"given":"Ah Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, Gyeongsang National University, Jinju 52828, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"afac220","DOI":"10.1093\/ageing\/afac220","article-title":"Sarcopenia definition, diagnosis and treatment: Consensus is growing","volume":"51","author":"Sayer","year":"2022","journal-title":"Age Ageing"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Beaudart, C., Zaaria, M., Pasleau, F., Reginster, J.Y., and Bruyere, O. (2017). Health Outcomes of Sarcopenia: A Systematic Review and Meta-Analysis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169548"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1532-5415.2004.52014.x","article-title":"The healthcare costs of sarcopenia in the United States","volume":"52","author":"Janssen","year":"2004","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_5","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_6","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_7","doi-asserted-by":"crossref","unstructured":"Chen, M., Wang, Y., Deng, S., Lian, Z., and Yu, K. (2022). Skeletal muscle oxidative stress and inflammation in aging: Focus on antioxidant and anti-inflammatory therapy. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.964130"},{"key":"ref_8","first-page":"12","article-title":"Chronic low-grade inflammation and age-related sarcopenia","volume":"15","author":"Beyer","year":"2012","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1152\/physrev.00033.2014","article-title":"Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting","volume":"95","author":"Tintignac","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.maturitas.2011.01.014","article-title":"Menopause and sarcopenia: A potential role for sex hormones","volume":"68","author":"Messier","year":"2011","journal-title":"Maturitas"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41413-021-00164-y","article-title":"Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration","volume":"9","author":"Wan","year":"2021","journal-title":"Bone Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rudrappa, S.S., Wilkinson, D.J., Greenhaff, P.L., Smith, K., Idris, I., and Atherton, P.J. (2016). Human Skeletal Muscle Disuse Atrophy: Effects on Muscle Protein Synthesis, Breakdown, and Insulin Resistance-A Qualitative Review. Front. Physiol., 7.","DOI":"10.3389\/fphys.2016.00361"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/s41467-020-20123-1","article-title":"Mechanisms of muscle atrophy and hypertrophy: Implications in health and disease","volume":"12","author":"Sartori","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nrd4467","article-title":"Muscle wasting in disease: Molecular mechanisms and promising therapies","volume":"14","author":"Cohen","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.clnu.2008.06.013","article-title":"Cachexia: A new definition","volume":"27","author":"Evans","year":"2008","journal-title":"Clin. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e13223","DOI":"10.1111\/acel.13223","article-title":"Animal models of sarcopenia","volume":"19","author":"Christian","year":"2020","journal-title":"Aging Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"97","DOI":"10.11005\/jbm.2020.27.2.97","article-title":"Rodent Model of Muscular Atrophy for Sarcopenia Study","volume":"27","author":"Baek","year":"2020","journal-title":"J. Bone Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.11005\/jbm.2021.28.3.179","article-title":"Two Types of Mouse Models for Sarcopenia Research: Senescence Acceleration and Genetic Modification Models","volume":"28","author":"Baek","year":"2021","journal-title":"J. Bone Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1353\/hpu.2019.0117","article-title":"Issues in the Use of Human Tissues to Support Precision Medicine","volume":"30","author":"Grizzle","year":"2019","journal-title":"J. Health Care Poor Underserved"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/nbt.3297","article-title":"Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy","volume":"33","author":"Chal","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1111\/j.1474-9726.2012.00869.x","article-title":"Modelling in vivo skeletal muscle ageing in vitro using three-dimensional bioengineered constructs","volume":"11","author":"Sharples","year":"2012","journal-title":"Aging Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/270725a0","article-title":"Serial passaging and differentiation of myogenic cells isolated from dystrophic mouse muscle","volume":"270","author":"Yaffe","year":"1977","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115517","DOI":"10.1016\/j.biopha.2023.115517","article-title":"Advances in research on cell models for skeletal muscle atrophy","volume":"167","author":"Li","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1096\/fj.04-2364com","article-title":"TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1\/MAFbx in skeletal muscle","volume":"19","author":"Li","year":"2005","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.biocel.2013.05.036","article-title":"Glucocorticoid-induced skeletal muscle atrophy","volume":"45","author":"Schakman","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s00424-018-2210-4","article-title":"In vitro experimental models for examining the skeletal muscle cell biology of exercise: The possibilities, challenges and future developments","volume":"471","author":"Carter","year":"2019","journal-title":"Pfl\u00fcgers Arch.-Eur. J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C886","DOI":"10.1152\/ajpcell.00586.2022","article-title":"Mimicking exercise in vitro: Effects of myotube contractions and mechanical stretch on omics","volume":"324","author":"Lautaoja","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ceb.2021.06.004","article-title":"Advanced models of human skeletal muscle differentiation, development and disease: Three-dimensional cultures, organoids and beyond","volume":"73","author":"Jalal","year":"2021","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Khodabukus, A. (2021). Tissue-Engineered Skeletal Muscle Models to Study Muscle Function, Plasticity, and Disease. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.619710"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1089\/ten.tea.2015.0093","article-title":"Endothelial Network Formation Within Human Tissue-Engineered Skeletal Muscle","volume":"21","author":"Gholobova","year":"2015","journal-title":"Tissue Eng. Part A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e22453","DOI":"10.1096\/fj.202200500R","article-title":"Tri-culture of spatially organizing human skeletal muscle cells, endothelial cells, and fibroblasts enhances contractile force and vascular perfusion of skeletal muscle tissues","volume":"36","author":"Kim","year":"2022","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"21251","DOI":"10.1038\/s41598-022-25758-2","article-title":"Genome-wide analysis of a cellular exercise model based on electrical pulse stimulation","volume":"12","author":"Lee","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/s41467-019-13869-w","article-title":"Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity","volume":"11","author":"Pillon","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41467-018-08023-x","article-title":"Bulk tissue cell type deconvolution with multi-subject single-cell expression reference","volume":"10","author":"Wang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/jcb.21833","article-title":"Dexamethasone and corticosterone induce similar, but not identical, muscle wasting responses in cultured L6 and C2C12 myotubes","volume":"105","author":"Menconi","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1007\/s00441-013-1655-1","article-title":"Are cultured human myotubes far from home?","volume":"354","author":"Aas","year":"2013","journal-title":"Cell Tissue Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"C643","DOI":"10.1152\/ajpcell.00135.2018","article-title":"Expansion capacity of human muscle progenitor cells differs by age, sex, and metabolic fuel preference","volume":"315","author":"Riddle","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Soriano-Arroquia, A., Clegg, P.D., Molloy, A.P., and Goljanek-Whysall, K. (2017). Preparation and Culture of Myogenic Precursor Cells\/Primary Myoblasts from Skeletal Muscle of Adult and Aged Humans. J. Vis. Exp., e55047.","DOI":"10.3791\/55047-v"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1101\/gad.173922.111","article-title":"Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state","volume":"25","author":"Lapasset","year":"2011","journal-title":"Genes Dev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lee, M.K., Choi, J.W., Choi, Y.H., and Nam, T.J. (2018). Pyropia yezoensis Protein Prevents Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes. Mar. Drugs, 16.","DOI":"10.3390\/md16120497"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bhatnagar, S., Panguluri, S.K., Gupta, S.K., Dahiya, S., Lundy, R.F., and Kumar, A. (2010). Tumor necrosis factor-alpha regulates distinct molecular pathways and gene networks in cultured skeletal muscle cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013262"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/2044-5040-2-2","article-title":"TNF-alpha- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism","volume":"2","author":"Zufferli","year":"2012","journal-title":"Skelet. Muscle"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Powrozek, T., Pigon-Zajac, D., Mazurek, M., Otieno, M.O., Rahnama-Hezavah, M., and Malecka-Massalska, T. (2022). TNF-alpha Induced Myotube Atrophy in C2C12 Cell Line Uncovers Putative Inflammatory-Related lncRNAs Mediating Muscle Wasting. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073878"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"C363","DOI":"10.1152\/ajpcell.00497.2008","article-title":"Calpain-1 is required for hydrogen peroxide-induced myotube atrophy","volume":"296","author":"McClung","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wu, X., Zhu, N., He, L., Xu, M., and Li, Y. (2024). 5\u2032-Cytimidine Monophosphate Ameliorates H2O2-Induced Muscular Atrophy in C2C12 Myotubes by Activating IRS-1\/Akt\/S6K Pathway. Antioxidants, 13.","DOI":"10.3390\/antiox13020249"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/1476-511X-12-104","article-title":"Saturated fatty acid palmitate-induced insulin resistance is accompanied with myotube loss and the impaired expression of health benefit myokine genes in C2C12 myotubes","volume":"12","author":"Yang","year":"2013","journal-title":"Lipids Health Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1096\/fj.14-252841","article-title":"Autophagy modulates amino acid signaling network in myotubes: Differential effects on mTORC1 pathway and the integrated stress response","volume":"29","author":"Yu","year":"2015","journal-title":"FASEB J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1007\/s10616-015-9920-7","article-title":"A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts","volume":"68","author":"Nozaki","year":"2016","journal-title":"Cytotechnology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"RP95229","DOI":"10.7554\/eLife.95229","article-title":"Senescent cells inhibit mouse myoblast differentiation via the SASP-lipid 15d-PGJ2 mediated modification and control of HRas","volume":"13","author":"Pundlik","year":"2024","journal-title":"eLife"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Boso, D., Maghin, E., Carraro, E., Giagante, M., Pavan, P., and Piccoli, M. (2020). Extracellular Matrix-Derived Hydrogels as Biomaterial for Different Skeletal Muscle Tissue Replacements. Materials, 13.","DOI":"10.3390\/ma13112483"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e44530","DOI":"10.7554\/eLife.44530","article-title":"A 3D culture model of innervated human skeletal muscle enables studies of the adult neuromuscular junction","volume":"8","author":"Bakooshli","year":"2019","journal-title":"eLife"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.lfs.2009.01.014","article-title":"Apoptotic signaling induced by H2O2-mediated oxidative stress in differentiated C2C12 myotubes","volume":"84","author":"Siu","year":"2009","journal-title":"Life Sci."},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41586-022-05535-x","article-title":"Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration","volume":"613","author":"Moiseeva","year":"2023","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature13013","article-title":"Geriatric muscle stem cells switch reversible quiescence into senescence","volume":"506","author":"Gutarra","year":"2014","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"0161","DOI":"10.34133\/bmr.0161","article-title":"Hydrogen Peroxide-Releasing Hydrogel-Mediated Cellular Senescence Model for Aging Research","volume":"29","author":"Wei","year":"2025","journal-title":"Biomater. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6555","DOI":"10.1038\/s41598-018-24959-y","article-title":"Premyogenic progenitors derived from human pluripotent stem cells expand in floating culture and differentiate into transplantable myogenic progenitors","volume":"8","author":"Narita","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s40659-023-00435-4","article-title":"iPSCs ameliorate hypoxia-induced autophagy and atrophy in C2C12 myotubes via the AMPK\/ULK1 pathway","volume":"56","author":"Cen","year":"2023","journal-title":"Biol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Nikolic, N., Bakke, S.S., Kase, E.T., Rudberg, I., Halle, I.F., Rustan, A.C., Thoresen, G.H., and Aas, V. (2012). Electrical pulse stimulation of cultured human skeletal muscle cells as an in vitro model of exercise. PLoS ONE, 7, Erratum in PLoS ONE 2013, 8. https:\/\/doi.org\/10.1371\/annotation\/270b432d-50ec-41f1-ad4d-ddd9f51f62a5.","DOI":"10.1371\/annotation\/270b432d-50ec-41f1-ad4d-ddd9f51f62a5"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"E1191\u20131204","DOI":"10.1152\/ajpendo.90280.2008","article-title":"Contractile C2C12 myotube model for studying exercise-inducible responses in skeletal muscle","volume":"295","author":"Nedachi","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Burch, N., Arnold, A.S., Item, F., Summermatter, S., Santos, G.B.S., Christe, M., Boutellier, U., Toigo, M., and Handschin, C. (2010). Electric pulse stimulation of cultured murine muscle cells reproduces gene expression changes of trained mouse muscle. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010970"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1007\/s00125-012-2454-z","article-title":"Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways","volume":"55","author":"Lambernd","year":"2012","journal-title":"Diabetologia"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.biomaterials.2018.08.058","article-title":"Electrical stimulation increases hypertrophy and metabolic flux in tissue-engineered human skeletal muscle","volume":"198","author":"Khodabukus","year":"2019","journal-title":"Biomaterials"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41574-022-00641-2","article-title":"Exerkines in health, resilience and disease","volume":"18","author":"Chow","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"E866\u2013878","DOI":"10.1152\/ajpendo.00104.2009","article-title":"Characterization of contraction-inducible CXC chemokines and their roles in C2C12 myocytes","volume":"297","author":"Nedachi","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.cell.2020.04.043","article-title":"Molecular Choreography of Acute Exercise","volume":"181","author":"Contrepois","year":"2020","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cmet.2017.12.001","article-title":"Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise","volume":"27","author":"Whitham","year":"2018","journal-title":"Cell Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/pmic.200601024","article-title":"Toward a better analysis of secreted proteins: The example of the myeloid cells secretome","volume":"7","author":"Chevallet","year":"2007","journal-title":"Proteomics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1016\/j.cell.2020.06.004","article-title":"Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise","volume":"181","author":"Sanford","year":"2020","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/BF02623630","article-title":"Longitudinal growth of skeletal myotubes in vitro in a new horizontal mechanical cell stimulator","volume":"25","author":"Vandenburgh","year":"1989","journal-title":"Vitr. Cell. Dev. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/mus.21473","article-title":"Involvement of PI3K\/Akt\/TOR pathway in stretch-induced hypertrophy of myotubes","volume":"41","author":"Sasai","year":"2010","journal-title":"Muscle Nerve"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10974-020-09589-0","article-title":"Mechanical loading of tissue engineered skeletal muscle prevents dexamethasone induced myotube atrophy","volume":"42","author":"Capel","year":"2021","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1113\/jphysiol.2008.164483","article-title":"Age-related differences in the dose-response relationship of muscle protein synthesis to resistance exercise in young and old men","volume":"587","author":"Kumar","year":"2009","journal-title":"J. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/acel.12578","article-title":"Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion","volume":"16","author":"Beezhold","year":"2017","journal-title":"Aging Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"581","DOI":"10.5483\/BMBRep.2021.54.12.151","article-title":"Molecular targets of exercise mimetics and their natural activators","volume":"54","author":"Jang","year":"2021","journal-title":"BMB Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.cell.2008.06.051","article-title":"AMPK and PPARdelta agonists are exercise mimetics","volume":"134","author":"Narkar","year":"2008","journal-title":"Cell"},{"key":"ref_80","first-page":"E1107\u20131112","article-title":"AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle","volume":"273","author":"Merrill","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.biochi.2021.11.004","article-title":"AICAR stimulates mitochondrial biogenesis and BCAA catabolic enzyme expression in C2C12 myotubes","volume":"195","author":"Hinkle","year":"2022","journal-title":"Biochimie"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"E1040\u20131045","DOI":"10.1152\/ajpendo.00242.2002","article-title":"Intermittent increases in cytosolic Ca2+ stimulate mitochondrial biogenesis in muscle cells","volume":"283","author":"Ojuka","year":"2002","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1126\/science.1071163","article-title":"Regulation of mitochondrial biogenesis in skeletal muscle by CaMK","volume":"296","author":"Wu","year":"2002","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1159\/000494655","article-title":"Interaction of CREB and PGC-1alpha Induces Fibronectin Type III Domain-Containing Protein 5 Expression in C2C12 Myotubes","volume":"50","author":"Yang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1210\/me.2003-0151","article-title":"The peroxisome proliferator-activated receptor beta\/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells","volume":"17","author":"Dressel","year":"2003","journal-title":"Mol. Endocrinol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/112_2013_17","article-title":"The role of mTORC1 in regulating protein synthesis and skeletal muscle mass in response to various mechanical stimuli","volume":"166","author":"Goodman","year":"2014","journal-title":"Rev. Physiol. Biochem. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1079\/PNS2004357","article-title":"Mechanotransduction and the regulation of protein synthesis in skeletal muscle","volume":"63","author":"Hornberger","year":"2004","journal-title":"Proc. Nutr. Soc."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"444","DOI":"10.15857\/ksep.2021.00577","article-title":"Differential Gene Expression in Cell Types of the Human Skeletal Muscle: A Bioinformatics-Based Meta-Review","volume":"30","author":"Baek","year":"2021","journal-title":"Exerc. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"131","DOI":"10.15857\/ksep.2021.30.2.131","article-title":"Machine Learning Application in Genomic, Exercise, and Vital Datasets","volume":"30","author":"Baek","year":"2021","journal-title":"Exerc. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.cell.2013.10.054","article-title":"A special population of regulatory T cells potentiates muscle repair","volume":"155","author":"Burzyn","year":"2013","journal-title":"Cell"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Melov, S., Tarnopolsky, M.A., Beckman, K., Felkey, K., and Hubbard, A. (2007). Resistance exercise reverses aging in human skeletal muscle. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000465"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1152\/japplphysiol.00435.2011","article-title":"Transcriptome signature of resistance exercise adaptations: Mixed muscle and fiber type specific profiles in young and old adults","volume":"112","author":"Raue","year":"2012","journal-title":"J. Appl. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.molcel.2019.02.026","article-title":"High-Dimensional Single-Cell Cartography Reveals Novel Skeletal Muscle-Resident Cell Populations","volume":"74","author":"Giordani","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41598-019-57110-6","article-title":"Single-cell transcriptional profiles in human skeletal muscle","volume":"10","author":"Rubenstein","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/biostatistics\/kxv027","article-title":"Methods that remove batch effects while retaining group differences may lead to exaggerated confidence in downstream analyses","volume":"17","author":"Nygaard","year":"2016","journal-title":"Biostatistics"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Varma, S., and Simon, R. (2006). Bias in error estimation when using cross-validation for model selection. BMC Bioinform., 7.","DOI":"10.1186\/1471-2105-7-91"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Ahmad, S.S., Ahmad, K., Lee, E.J., Shaikh, S., and Choi, I. (2021). Computational Identification of Dithymoquinone as a Potential Inhibitor of Myostatin and Regulator of Muscle Mass. Molecules, 26.","DOI":"10.3390\/molecules26175407"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"141734","DOI":"10.1016\/j.ijbiomac.2025.141734","article-title":"Phosphorylation-driven regulation of SIRT1 in muscle senescence: Insights from molecular dynamics simulation and experimental validation","volume":"306","author":"Liu","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"11714","DOI":"10.1038\/s41598-025-96108-1","article-title":"Selection of optimal human myoblasts based on patient related factors influencing proliferation and differentiation capacity","volume":"15","author":"Englich","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"8296150","DOI":"10.1155\/2016\/8296150","article-title":"Proliferation of Human Primary Myoblasts Is Associated with Altered Energy Metabolism in Dependence on Ageing In Vivo and In Vitro","volume":"2016","author":"Eimre","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.stem.2015.09.001","article-title":"Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects","volume":"17","author":"Mertens","year":"2015","journal-title":"Cell Stem Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8609\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:16:29Z","timestamp":1790655389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,26]]},"references-count":102,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198609"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198609","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,26]]}}}