Lee, I.-M. et al. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 380, 219–229 (2012).
Google Scholar
Knight, J. A. Physical inactivity: associated diseases and disorders. Ann. Clin. Lab. Sci. 42, 320–337 (2012).
Kyu, H. H. et al. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. BMJ 354, i3857 (2016).
Google Scholar
Pate, R. R. et al. Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 273, 402–407 (1995).
Google Scholar
Caspersen, C. J., Powell, K. E. & Christenson, G. M. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. Wash. DC 1974 100, 126–131 (1985).
Google Scholar
Gleeson, M. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615 (2011).
Google Scholar
Kujala, U. M. Evidence on the effects of exercise therapy in the treatment of chronic disease. Br. J. Sports Med. 43, 550–555 (2009).
Google Scholar
Pedersen, B. K. & Saltin, B. Exercise as medicine—evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand. J. Med. Sci. Sports 25, 1–72 (2015).
Google Scholar
Heinonen, I. et al. Organ-specific physiological responses to acute physical exercise and long-term training in humans. Physiology 29, 421–436 (2014).
Google Scholar
McGee, S. L. & Hargreaves, M. Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit. Nat. Rev. Endocrinol. 16, 495–505 (2020).
Google Scholar
Ruegsegger, G. N. & Booth, F. W. Health benefits of exercise. Cold Spring Harb. Perspect. Med. 8, a029694 (2018).
Google Scholar
Safdar, A., Saleem, A. & Tarnopolsky, M. A. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat. Rev. Endocrinol. 12, 504–517 (2016).
Google Scholar
Safdar, A. & Tarnopolsky, M. A. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb. Perspect. Med. 8, a029827 (2018).
Google Scholar
Chow, L. S. et al. Exerkines in health, resilience and disease. Nat. Rev. Endocrinol. 18, 273–289 (2022).
Google Scholar
Jin, L., Diaz-Canestro, C., Wang, Y., Tse, M. A. & Xu, A. Exerkines and cardiometabolic benefits of exercise: from bench to clinic. EMBO Mol. Med. 16, 432–444 (2024).
Google Scholar
Ashcroft, S. P., Stocks, B., Egan, B. & Zierath, J. R. Exercise induces tissue-specific adaptations to enhance cardiometabolic health. Cell Metab. 36, 278–300 (2024).
Google Scholar
Li, V. L. et al. An exercise-inducible metabolite that suppresses feeding and obesity. Nature 606, 785–790 (2022).
Google Scholar
Chen, H. et al. Exercise training maintains cardiovascular health: signaling pathways involved and potential therapeutics. Signal Transduct. Target. Ther. 7, 306 (2022).
Google Scholar
Hojman, P., Gehl, J., Christensen, J. F. & Pedersen, B. K. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 27, 10–21 (2018).
Google Scholar
Tian, D. & Meng, J. Exercise for prevention and relief of cardiovascular disease: prognoses, mechanisms, and approaches. Oxid. Med. Cell. Longev. 2019, 1–11 (2019).
Wang, Q. & Zhou, W. Roles and molecular mechanisms of physical exercise in cancer prevention and treatment. J. Sport Health Sci. 10, 201–210 (2021).
Google Scholar
Chen, J., Zhou, R., Feng, Y. & Cheng, L. Molecular mechanisms of exercise contributing to tissue regeneration. Signal Transduct. Target. Ther. 7, 1–24 (2022).
Google Scholar
Ji, S. et al. Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases. Signal Transduct. Target. Ther. 8, 116 (2023).
Google Scholar
Moreira, J. B. N., Wohlwend, M. & Wisløff, U. Exercise and cardiac health: physiological and molecular insights. Nat. Metab. 2, 829–839 (2020).
Google Scholar
Gubert, C. & Hannan, A. J. Exercise mimetics: harnessing the therapeutic effects of physical activity. Nat. Rev. Drug Discov. 20, 862–879 (2021).
Google Scholar
Darragh, I. A. J. & Egan, B. Considerations for exerkine research focusing on the response to exercise training. J. Sport Health Sci. 13, 130–132 (2024).
Google Scholar
Reghupaty, S. C., Dall, N. R. & Svensson, K. J. Hallmarks of the metabolic secretome. Trends Endocrinol. Metab. 35, 49–61 (2024).
Google Scholar
Baker, S. A. & Rutter, J. Metabolites as signalling molecules. Nat. Rev. Mol. Cell Biol. 24, 355–374 (2023).
Google Scholar
Lone, J. B., Long, J. Z. & Svensson, K. J. Size matters: the biochemical logic of ligand type in endocrine crosstalk. Life Metab. 3, load048 (2024).
Google Scholar
Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
Google Scholar
Xu, X. et al. Follistatin-like 1 as a novel adipomyokine related to insulin resistance and physical activity. J. Clin. Endocrinol. Metab. 105, e4499–e4509 (2020).
Google Scholar
Nam, J. S. et al. Follistatin‐like 1 is a myokine regulating lipid mobilization during endurance exercise and recovery. Obesity 32, 352–362 (2024).
Google Scholar
Kon, M., Ebi, Y. & Nakagaki, K. Effects of acute sprint interval exercise on follistatin-like 1 and apelin secretions. Arch. Physiol. Biochem. 127, 223–227 (2021).
Google Scholar
Nam, H.-J., Kim, I., Bowie, J. U. & Kim, S. Metazoans evolved by taking domains from soluble proteins to expand intercellular communication network. Sci. Rep. 5, 9576 (2015).
Google Scholar
Contrepois, K. et al. Molecular choreography of acute exercise. Cell 181, 1112–1130.e16 (2020).
Google Scholar
Mi, M. Y. et al. Plasma proteomic kinetics in response to acute exercise. Mol. Cell. Proteom. 22, 100601 (2023).
Google Scholar
Parker, B. L. et al. Multiplexed temporal quantification of the exercise-regulated plasma peptidome. Mol. Cell. Proteom. 16, 2055–2068 (2017).
Google Scholar
Robbins, J. M. et al. Human plasma proteomic profiles indicative of cardiorespiratory fitness. Nat. Metab. 3, 786–797 (2021).
Google Scholar
Robbins, J. M. et al. Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations. JCI Insight 8, e165867 (2023).
Google Scholar
Wei, W. et al. Organism-wide, cell-type-specific secretome mapping of exercise training in mice. Cell Metab. 35, 1261–1279.e11 (2023).
Google Scholar
Brooks, G. A. The science and translation of Lactate shuttle theory. Cell Metab. 27, 757–785 (2018).
Google Scholar
Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).
Google Scholar
Rabinowitz, J. D. & Enerbäck, S. Lactate: the ugly duckling of energy metabolism. Nat. Metab. 2, 566–571 (2020).
Google Scholar
Brooks, G. A. Lactate as a fulcrum of metabolism. Redox Biol. 35, 101454 (2020).
Google Scholar
Brooks, G. A. et al. Lactate as a major myokine and exerkine. Nat. Rev. Endocrinol. 18, 712–712 (2022).
Google Scholar
Howarth, K. R., LeBlanc, P. J., Heigenhauser, G. J. F. & Gibala, M. J. Effect of endurance training on muscle TCA cycle metabolism during exercise in humans. J. Appl. Physiol. 97, 579–584 (2004).
Google Scholar
Schranner, D., Kastenmüller, G., Schönfelder, M., Römisch-Margl, W. & Wackerhage, H. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med. – Open 6, 11 (2020).
Google Scholar
Ferreira, L. M. R. et al. Intermediary metabolism: an intricate network at the crossroads of cell fate and function. Biochim. Biophys. Acta BBA – Mol. Basis Dis. 1866, 165887 (2020).
Google Scholar
Veerappa, S. & McClure, J. Intermediary metabolism. Anaesth. Intensive Care Med. 21, 162–167 (2020).
Google Scholar
Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33a37 (2010).
Abdelmoez, A. M. et al. Cell selectivity in succinate receptor SUCNR1 /GPR91 signaling in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 324, E289–E298 (2023).
Google Scholar
Reddy, A. et al. pH-Gated succinate secretion regulates muscle remodeling in response to exercise. Cell 183, 62–75.e17 (2020).
Google Scholar
Wang, T. et al. Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling. EMBO Rep. 20, e47892 (2019).
Google Scholar
Murphy, M. P. & O’Neill, L. A. J. Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell 174, 780–784 (2018).
Google Scholar
Reddy, A. et al. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes. Nat. Metab. 6, 567–577 (2024).
Google Scholar
Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e3 (2018).
Google Scholar
Kitase, Y. et al. β-aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep. 22, 1531–1544 (2018).
Google Scholar
Roberts, L. D. et al. β-aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).
Google Scholar
Morville, T., Sahl, R. E., Moritz, T., Helge, J. W. & Clemmensen, C. Plasma metabolome profiling of resistance exercise and endurance exercise in humans. Cell Rep. 33, 108554 (2020).
Google Scholar
Nemeth, K., Bayraktar, R., Ferracin, M. & Calin, G. A. Non-coding RNAs in disease: from mechanisms to therapeutics. Nat. Rev. Genet. 25, 211–232 (2024).
Google Scholar
Statello, L., Guo, C.-J., Chen, L.-L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).
Google Scholar
De Goede, O. M. et al. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease. Cell 184, 2633–2648.e19 (2021).
Google Scholar
Guo, Z. et al. Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci. Rep. 4, 5150 (2014).
Google Scholar
Just, J. et al. Blood flow-restricted resistance exercise alters the surface profile, miRNA cargo and functional impact of circulating extracellular vesicles. Sci. Rep. 10, 5835 (2020).
Google Scholar
Ma, C. et al. Moderate exercise enhances endothelial progenitor cell exosomes release and function. Med. Sci. Sports Exerc. 50, 2024–2032 (2018).
Google Scholar
Warnier, G. et al. Effects of a 6-wk sprint interval training protocol at different altitudes on circulating extracellular vesicles. Med. Sci. Sports Exerc. 55, 46–54 (2023).
Google Scholar
Bye, A. et al. Circulating microRNAs and aerobic fitness – the HUNT study. PLoS ONE 8, e57496 (2013).
Google Scholar
Rutkovskiy, A. et al. Circulating microRNA-210 concentrations in patients with acute heart failure: data from the Akershus cardiac examination 2 study. Clin. Chem. 67, 889–898 (2021).
Google Scholar
Røsjø, H. et al. Prognostic value of circulating MicroRNA-210 levels in patients with moderate to severe aortic stenosis. PLoS One 9, e91812 (2014).
Google Scholar
Bye, A. et al. Circulating microRNAs predict future fatal myocardial infarction in healthy individuals—the HUNT study. J. Mol. Cell. Cardiol. 97, 162–168 (2016).
Google Scholar
Stølen, T. O. et al. Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction. J. Mol. Cell. Cardiol. 148, 106–119 (2020).
Google Scholar
Bei, Y. et al. Exercise-induced miR-210 promotes cardiomyocyte proliferation and survival and mediates exercise-induced cardiac protection against ischemia/reperfusion injury. Research 7, 0327 (2024).
Google Scholar
Kotewitsch, M., Heimer, M., Schmitz, B. & Mooren, F. C. Non-coding RNAs in exercise immunology: a systematic review. J. Sport Health Sci. (2023).
Zhang, T. et al. miR-143 regulates memory T cell differentiation by reprogramming T cell metabolism. J. Immunol. 201, 2165–2175 (2018).
Google Scholar
Ye, Z. et al. Regulation of miR-181a expression in T cell aging. Nat. Commun. 9, 3060 (2018).
Google Scholar
Miranda, K. et al. MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages. Int. J. Obes. 42, 1140–1150 (2018).
Google Scholar
Silva, G. J. J., Bye, A., El Azzouzi, H. & Wisløff, U. MicroRNAs as important regulators of exercise adaptation. Prog. Cardiovasc. Dis. 60, 130–151 (2017).
Google Scholar
Russell, A. P. et al. Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short‐term endurance training. J. Physiol. 591, 4637–4653 (2013).
Google Scholar
Safdar, A., Abadi, A., Akhtar, M., Hettinga, B. P. & Tarnopolsky, M. A. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6J male mice. PLOS One 4, e5610 (2009).
Google Scholar
Bonilauri, B. & Dallagiovanna, B. Long non-coding RNAs are differentially expressed after different exercise training programs. Front. Physiol. 11, 567614 (2020).
Google Scholar
Wohlwend, M. et al. The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging. Sci. Transl. Med. 13, eabc7367 (2021).
Google Scholar
Trewin, A. J. et al. Long non-coding RNA Tug1 modulates mitochondrial and myogenic responses to exercise in skeletal muscle. BMC Biol. 20, 164 (2022).
Google Scholar
Chen, W., Ye, Q. & Dong, Y. Long term exercise-derived exosomal LncRNA CRNDE mitigates myocardial infarction injury through miR-489-3p/Nrf2 signaling axis. Nanomed. Nanotechnol. Biol. Med. 55, 102717 (2024).
Google Scholar
Done, A. J. & Traustadóttir, T. Nrf2 mediates redox adaptations to exercise. Redox Biol. 10, 191–199 (2016).
Google Scholar
Gao, R. et al. Long noncoding RNA cardiac physiological hypertrophy-associated regulator induces cardiac physiological hypertrophy and promotes functional recovery after myocardial ischemia-reperfusion injury. Circulation 144, 303–317 (2021).
Google Scholar
Li, H. et al. lncExACT1 and DCHS2 regulate physiological and pathological cardiac growth. Circulation 145, 1218–1233 (2022).
Google Scholar
Zhu, Y. et al. Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning. J. Adv. Res. 46, 113–121 (2023).
Google Scholar
Wang, L. et al. Exercise-induced circular RNA circUtrn is required for cardiac physiological hypertrophy and prevents myocardial ischaemia–reperfusion injury. Cardiovasc. Res. 119, 2638–2652 (2023).
Google Scholar
Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).
Google Scholar
Sen, R., Ghosal, S., Das, S., Balti, S. & Chakrabarti, J. Competing endogenous RNA: the key to posttranscriptional regulation. Sci. World J. 2014, 896206 (2014).
Google Scholar
Nie, M., Liu, Q. & Yan, C. Construction of a novel lncRNA-miRNA-mRNA competing endogenous RNA network in muscle in response to exercise training. Gen. Physiol. Biophys. 42, 123–133 (2023).
Google Scholar
Wu, J. et al. LncRNA/miRNA/mRNA ceRNA network analysis in spinal cord injury rat with physical exercise therapy. PeerJ 10, e13783 (2022).
Google Scholar
Wang, L. et al. METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury. Nat. Commun. 13, 6762 (2022).
Google Scholar
Yan, L. et al. Physical exercise prevented stress‐induced anxiety via improving brain RNA methylation. Adv. Sci. 9, 2105731 (2022).
Google Scholar
Subbotina, E. et al. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc. Natl Acad. Sci. 112, 16042–16047 (2015).
Google Scholar
Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).
Google Scholar
Ingerslev, B. et al. Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP. Mol. Metab. 6, 1286–1295 (2017).
Google Scholar
Hou, Z. et al. Longterm exercise-derived exosomal miR-342-5p: a novel exerkine for cardioprotection. Circ. Res. 124, 1386–1400 (2019).
Google Scholar
Davis, B. D. & Tai, P.-C. The mechanism of protein secretion across membranes. Nature 283, 433–438 (1980).
Google Scholar
Hegde, R. S. & Keenan, R. J. The mechanisms of integral membrane protein biogenesis. Nat. Rev. Mol. Cell Biol. 23, 107–124 (2022).
Google Scholar
Hosoya, M. et al. Molecular and functional characteristics of APJ. J. Biol. Chem. 275, 21061–21067 (2000).
Google Scholar
Kawamata, Y. et al. Molecular properties of apelin: tissue distribution and receptor binding. Biochim. Biophys. Acta BBA – Mol. Cell Res. 1538, 162–171 (2001).
Google Scholar
Kelly, R. B. Pathways of protein secretion in eukaryotes. Science 230, 25–32 (1985).
Google Scholar
Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nat. Rev. Mol. Cell Biol. 10, 148–155 (2009).
Google Scholar
Rabouille, C. Pathways of unconventional protein secretion. Trends Cell Biol. 27, 230–240 (2017).
Google Scholar
Sahlin, K., Katz, A. & Henriksson, J. Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem. J. 245, 551–556 (1987).
Google Scholar
Spriet, L. L., Howlett, R. A. & Heigenhauser, G. J. F. An enzymatic approach to lactate production in human skeletal muscle during exercise. Med. Sci. Sports Exerc. 32, 756–763 (2000).
Google Scholar
Gould, S. J. & Raposo, G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles 2, 20389 (2013).
Google Scholar
Xu, R. et al. Extracellular vesicles in cancer—implications for future improvements in cancer care. Nat. Rev. Clin. Oncol. 15, 617–638 (2018).
Google Scholar
Hill, A. F. Extracellular vesicles and neurodegenerative diseases. J. Neurosci. 39, 9269–9273 (2019).
Google Scholar
Buzas, E. I. The roles of extracellular vesicles in the immune system. Nat. Rev. Immunol. 23, 236–250 (2023).
Google Scholar
Hendrix, A. et al. Extracellular vesicle analysis. Nat. Rev. Methods Prim. 3, 56 (2023).
Google Scholar
Frühbeis, C., Helmig, S., Tug, S., Simon, P. & Krämer‐Albers, E. Physical exercise induces rapid release of small extracellular vesicles into the circulation. J. Extracell. Vesicles 4, 28239 (2015).
Google Scholar
McIlvenna, L. C. et al. Single vesicle analysis reveals the release of tetraspanin positive extracellular vesicles into circulation with high intensity intermittent exercise. J. Physiol. 601, 5093–5106 (2023).
Google Scholar
Delgado-Peraza, F. et al. Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer’s disease. Alzheimers Res. Ther. 15, 156 (2023).
Google Scholar
Ma, S. et al. Skeletal muscle-derived extracellular vesicles transport glycolytic enzymes to mediate muscle-to-bone crosstalk. Cell Metab. 35, 2028–2043.e7 (2023).
Google Scholar
Peng, B. et al. Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia. Mol. Ther. 31, 1418–1436 (2023).
Google Scholar
Whitham, M. et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 27, 237–251.e4 (2018).
Google Scholar
Vechetti, I. J., Valentino, T., Mobley, C. B. & McCarthy, J. J. The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise. J. Physiol. 599, 845–861 (2021).
Google Scholar
Bayraktar, R., Van Roosbroeck, K. & Calin, G. A. Cell‐to‐cell communication: microRNAs as hormones. Mol. Oncol. 11, 1673–1686 (2017).
Google Scholar
Liu, T. et al. EVmiRNA: a database of miRNA profiling in extracellular vesicles. Nucleic Acids Res 47, D89–D93 (2019).
Google Scholar
Mittelbrunn, M. & Sánchez-Madrid, F. Intercellular communication: diverse structures for exchange of genetic information. Nat. Rev. Mol. Cell Biol. 13, 328–335 (2012).
Google Scholar
Doncheva, A. I. et al. Extracellular vesicles and microRNAs are altered in response to exercise, insulin sensitivity and overweight. Acta Physiol. 236, e13862 (2022).
Google Scholar
Peng, H. et al. A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis. Cell Metab. 34, 1168–1182.e6 (2022).
Google Scholar
Islam, M. R. et al. Exercise hormone irisin is a critical regulator of cognitive function. Nat. Metab. 3, 1058–1070 (2021).
Google Scholar
Lourenco, M. V. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat. Med. 25, 165–175 (2019).
Google Scholar
Wrann, C. D. et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 18, 649–659 (2013).
Google Scholar
Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).
Google Scholar
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
Google Scholar
Aoi, W. et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62, 882–889 (2013).
Google Scholar
Jørgensen, L. H. et al. SPARC interacts with actin in skeletal muscle in vitro and in vivo. Am. J. Pathol. 187, 457–474 (2017).
Google Scholar
Gu, H. et al. Soluble klotho improves hepatic glucose and lipid homeostasis in type 2 diabetes. Mol. Ther. Methods Clin. Dev. 18, 811–823 (2020).
Google Scholar
Rao, Z., Zheng, L., Huang, H., Feng, Y. & Shi, R. α-Klotho expression in mouse tissues following acute exhaustive exercise. Front. Physiol. 10, 1498 (2019).
Google Scholar
Seldin, M. M., Peterson, J. M., Byerly, M. S., Wei, Z. & Wong, G. W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J. Biol. Chem. 287, 11968–11980 (2012).
Google Scholar
De Nardo, W. et al. Proteomic analysis reveals exercise training induced remodelling of hepatokine secretion and uncovers syndecan-4 as a regulator of hepatic lipid metabolism. Mol. Metab. 60, 101491 (2022).
Google Scholar
Chong, M. C., Silva, A., James, P. F., Wu, S. S. X. & Howitt, J. Exercise increases the release of NAMPT in extracellular vesicles and alters NAD + activity in recipient cells. Aging Cell 21, e13647 (2022).
Orange, S. T. et al. Acute aerobic exercise‐conditioned serum reduces colon cancer cell proliferation in vitro through interleukin‐6‐induced regulation of DNA damage. Int. J. Cancer 151, 265–274 (2022).
Google Scholar
Kasper, A. M., Turner, D. C., Martin, N. R. W. & Sharples, A. P. Mimicking exercise in three-dimensional bioengineered skeletal muscle to investigate cellular and molecular mechanisms of physiological adaptation. J. Cell. Physiol. 233, 1985–1998 (2018).
Google Scholar
Lautaoja, J. H. et al. Mimicking exercise in vitro: effects of myotube contractions and mechanical stretch on omics. Am. J. Physiol. -Cell Physiol. 324, C886–C892 (2023).
Google Scholar
Watanabe, L. P. & Riddle, N. C. New opportunities: Drosophila as a model system for exercise research. J. Appl. Physiol. 127, 482–490 (2019).
Google Scholar
Laranjeiro, R., Harinath, G., Burke, D., Braeckman, B. P. & Driscoll, M. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol. 15, 30 (2017).
Google Scholar
Laranjeiro, R. et al. Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration. Proc. Natl Acad. Sci. 116, 23829–23839 (2019).
Google Scholar
Poole, D. C. et al. Guidelines for animal exercise and training protocols for cardiovascular studies. Am. J. Physiol. Heart Circ. Physiol. 318, H1100–H1138 (2020).
Google Scholar
Crane, J. D. et al. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging. Aging Cell 14, 625–634 (2015).
Google Scholar
Chaweewannakorn, C. et al. Exercise‐evoked intramuscular neutrophil‐endothelial interactions support muscle performance and GLUT4 translocation: a mouse gnawing model study. J. Physiol. 598, 101–122 (2020).
Google Scholar
Correia, J. C. et al. Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity. Cell Metab. 33, 2215–2230.e8 (2021).
Google Scholar
Dray, C. et al. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab. 8, 437–445 (2008).
Google Scholar
Iwabu, M. et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319 (2010).
Google Scholar
Loro, E. et al. Effect of interleukin-15 receptor alpha ablation on the metabolic responses to moderate exercise simulated by in vivo isometric muscle contractions. Front. Physiol. 10, 1439 (2019).
Google Scholar
Nyasha, M. R. et al. Effects of CX3CR1 and CXCR2 antagonists on running-dependent intramuscular neutrophil recruitments and myokine upregulation. Am. J. Physiol. Endocrinol. Metab. 324, E375–E389 (2023).
Google Scholar
Takahashi, H. et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat. Metab. 1, 291–303 (2019).
Google Scholar
Vinel, C. et al. The exerkine apelin reverses age-associated sarcopenia. Nat. Med. 24, 1360–1371 (2018).
Google Scholar
Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).
Google Scholar
Yamauchi, T. et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332–339 (2007).
Google Scholar
Liu, Y. et al. TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise. Nature 578, 605–609 (2020).
Google Scholar
Bjørnholt, J. V. et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care 22, 45–49 (1999).
Google Scholar
Rao Kondapally Seshasai, S. et al. The emerging risk factors collaboration. diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).
Halbgebauer, D. et al. Latent TGFβ-binding proteins regulate UCP1 expression and function via TGFβ2. Mol. Metab. 53, 101336 (2021).
Google Scholar
Gumucio, J. P., Sugg, K. B. & Mendias, C. L. TGF-β superfamily signaling in muscle and tendon adaptation to resistance exercise. Exerc. Sport Sci. Rev. 43, 93–99 (2015).
Google Scholar
Budagian, V., Bulanova, E., Paus, R. & Bulfonepaus, S. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev. 17, 259–280 (2006).
Google Scholar
Quinn, L. S. Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition. J. Anim. Sci. 86, E75–E83 (2008).
Google Scholar
Tamura, Y. et al. Upregulation of circulating IL-15 by treadmill running in healthy individuals: Is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr. J. 58, 211–215 (2011).
Google Scholar
Quinn, L. S., Anderson, B. G., Strait-Bodey, L., Stroud, A. M. & Argilés, J. M. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am. J. Physiol. Endocrinol. Metab. 296, E191–E202 (2009).
Google Scholar
Nielsen, A. R. et al. Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J. Clin. Endocrinol. Metab. 93, 4486–4493 (2008).
Google Scholar
Matsukawa, N. et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc. Natl Acad. Sci. 96, 7403–7408 (1999).
Google Scholar
Yuan, Y. et al. Succinate promotes skeletal muscle protein synthesis via Erk1/2 signaling pathway. Mol. Med. Rep. 16, 7361–7366 (2017).
Google Scholar
Gordan, R., Gwathmey, J. K. & Xie, L.-H. Autonomic and endocrine control of cardiovascular function. World J. Cardiol. 7, 204 (2015).
Google Scholar
Lavin, K. M. et al. State of knowledge on molecular adaptations to exercise in humans: historical perspectives and future directions. Compr. Physiol. 12, 3193–3279 (2022).
Lu, L., Wu, D., Li, L. & Chen, L. Apelin/APJ system: a bifunctional target for cardiac hypertrophy. Int. J. Cardiol. 230, 164–170 (2017).
Google Scholar
Bei, Y. et al. Lymphangiogenesis contributes to exercise-induced physiological cardiac growth. J. Sport Health Sci. 11, 466–478 (2022).
Google Scholar
Lee, H. W. et al. Effects of exercise training and TrkB blockade on cardiac function and BDNF-TrkB signaling postmyocardial infarction in rats. Am. J. Physiol. Heart Circ. Physiol. 315, H1821–H1834 (2018).
Google Scholar
Lee, H. W., Ahmad, M., Wang, H.-W. & Leenen, F. H. H. Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction: cardiac brain-derived neurotrophic factor post myocardial infarction. Exp. Physiol. 102, 314–328 (2017).
Google Scholar
Slagsvold, K. H. et al. Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: a randomized trial. Int. J. Cardiol. 177, 409–417 (2014).
Google Scholar
Przyklenk, K. & Whittaker, P. Remote ischemic preconditioning: current knowledge, unresolved questions, and future priorities. J. Cardiovasc. Pharmacol. Ther. 16, 255–259 (2011).
Google Scholar
Reboll, M. R. et al. Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase. Science 376, 1343–1347 (2022).
Google Scholar
Cai, M.-X. et al. Exercise training activates neuregulin 1/ErbB signaling and promotes cardiac repair in a rat myocardial infarction model. Life Sci. 149, 1–9 (2016).
Google Scholar
Scheja, L. & Heeren, J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat. Rev. Endocrinol. 15, 507–524 (2019).
Google Scholar
Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).
Google Scholar
Lavie, C. J., Milani, R. V. & Ventura, H. O. Obesity and cardiovascular disease. J. Am. Coll. Cardiol. 53, 1925–1932 (2009).
Google Scholar
Jedrychowski, M. P. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab. 22, 734–740 (2015).
Google Scholar
Raschke, S. et al. Evidence against a beneficial effect of Irisin in humans. PLoS One 8, e73680 (2013).
Google Scholar
Timmons, J. A., Baar, K., Davidsen, P. K. & Atherton, P. J. Is irisin a human exercise gene? Nature 488, E9–E10 (2012).
Google Scholar
Kim, H. et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175, 1756–1768.e17 (2018).
Google Scholar
Mu, A. et al. Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α. Mol. Cell 83, 1903–1920.e12 (2023).
Google Scholar
Agudelo, L. Z. et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. Cell Metab. 27, 378–392.e5 (2018).
Google Scholar
Baht, G. S. et al. Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism. Nat. Metab. 2, 278–289 (2020).
Google Scholar
Jung, T. W. et al. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice. Exp. Mol. Med. 50, 1–11 (2018).
Google Scholar
Lee, D. E. et al. Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling. Nat. Commun. 13, 7613 (2022).
Google Scholar
Knudsen, J. G. et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS ONE 9, e84910 (2014).
Google Scholar
Kim, K. H. et al. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One 8, e63517 (2013).
Google Scholar
Fisher, F. M. & Maratos-Flier, E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 78, 223–241 (2016).
Google Scholar
Geng, L. et al. Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell Rep. 26, 2738–2752.e4 (2019).
Google Scholar
Chilibeck, P. D., Sale, D. G. & Webber, C. E. Exercise and bone mineral density. Sports Med 19, 103–122 (1995).
Google Scholar
Audzeyenka, I. et al. β-Aminoisobutyric acid (L-BAIBA) is a novel regulator of mitochondrial biogenesis and respiratory function in human podocytes. Sci. Rep. 13, 766 (2023).
Google Scholar
Colaianni, G. et al. The myokine irisin increases cortical bone mass. Proc. Natl Acad. Sci. 112, 12157–12162 (2015).
Google Scholar
Blazek, A. D. et al. Exercise-driven metabolic pathways in healthy cartilage. Osteoarthr. Cartil. 24, 1210–1222 (2016).
Google Scholar
Wu, D. et al. The blood–brain barrier: structure, regulation, and drug delivery. Signal Transduct. Target. Ther. 8, 217 (2023).
Google Scholar
Gómez-Pinilla, F., Ying, Z., Roy, R. R., Molteni, R. & Edgerton, V. R. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J. Neurophysiol. 88, 2187–2195 (2002).
Google Scholar
Kam, T.-I. et al. Amelioration of pathologic α-synuclein-induced Parkinson’s disease by irisin. Proc. Natl Acad. Sci. 119, e2204835119 (2022).
Google Scholar
Lambertus, M. et al. L-lactate induces neurogenesis in the mouse ventricular-subventricular zone via the lactate receptor HCA1. Acta Physiol. 231, e13587 (2021).
Google Scholar
Morland, C. et al. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat. Commun. 8, 15557 (2017).
Google Scholar
Zhang, P. et al. Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model. J. Neuroeng. Rehabil. 10, 43 (2013).
Google Scholar
Yang, L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158–1166 (2017).
Google Scholar
Moon, H. Y. et al. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab. 24, 332–340 (2016).
Google Scholar
Park, C. et al. Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice. Nat. Aging 3, 1067–1078 (2023).
Google Scholar
Schroer, A. B. et al. Platelet factors attenuate inflammation and rescue cognition in ageing. Nature 620, 1071–1079 (2023).
Google Scholar
Leiter, O. et al. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat. Commun. 14, 4375 (2023).
Google Scholar
Leiter, O. et al. Exercise-induced activated platelets increase adult hippocampal precursor proliferation and promote neuronal differentiation. Stem Cell Rep. 12, 667–679 (2019).
Google Scholar
De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).
Google Scholar
Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020).
Google Scholar
Binder, D. K. & Scharfman, H. E. Brain-derived neurotrophic factor. Growth Factors 22, 123–131 (2004).
Google Scholar
Pedersen, B. K. Physical activity and muscle–brain crosstalk. Nat. Rev. Endocrinol. 15, 383–392 (2019).
Google Scholar
Brindle, N. P. J., Saharinen, P. & Alitalo, K. Signaling and Functions of Angiopoietin-1 in Vascular Protection. Circ. Res. 98, 1014–1023 (2006).
Google Scholar
McClung, J. M. et al. Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment. Front. Physiol. 6, 161 (2015).
Lauritzen, K. H. et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb. Cortex 24, 2784–2795 (2014).
Google Scholar
Maugeri, G. et al. The role of exercise on peripheral nerve regeneration: from animal model to clinical application. Heliyon 7, e08281 (2021).
Google Scholar
Udina, E., Puigdemasa, A. & Navarro, X. Passive and active exercise improve regeneration and muscle reinnervation after peripheral nerve injury in the rat. Muscle Nerve 43, 500–509 (2011).
Google Scholar
Houle, J. D. & Côté, M. Axon regeneration and exercise‐dependent plasticity after spinal cord injury. Ann. N. Y. Acad. Sci. 1279, 154–163 (2013).
Google Scholar
Park, J.-S. & Höke, A. Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors. PLoS One 9, e90245 (2014).
Google Scholar
Preuss, C. V. & Anjum, F. Tocilizumab. [Updated 2022 Sep 21]. StatPearls [Internet] (2023).
Kistner, T. M., Pedersen, B. K. & Lieberman, D. E. Interleukin 6 as an energy allocator in muscle tissue. Nat. Metab. 4, 170–179 (2022).
Google Scholar
Wedell-Neergaard, A.-S. et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 29, 844–855.e3 (2019).
Google Scholar
Trinh, B. et al. Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men. Cell Rep. Med. 2, 100396 (2021).
Google Scholar
Bay, M. L. et al. Human immune cell mobilization during exercise: effect of IL‐6 receptor blockade. Exp. Physiol. 105, 2086–2098 (2020).
Google Scholar
Christensen, R. H. et al. Aerobic exercise induces cardiac fat loss and alters cardiac muscle mass through an interleukin-6 receptor–dependent mechanism: cardiac analysis of a double-blind randomized controlled clinical trial in abdominally obese humans. Circulation 140, 1684–1686 (2019).
Google Scholar
Trinh, B. et al. Amino acid metabolism and protein turnover in lean and obese humans during exercise—effect of IL-6 receptor blockade. J. Clin. Endocrinol. Metab. 107, 1854–1864 (2022).
Google Scholar
Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 23, 554–562 (2016).
Google Scholar
Djurhuus, S. S. et al. Exercise training to increase tumour natural killer‐cell infiltration in men with localised prostate cancer: a randomised controlled trial. BJU Int 131, 116–124 (2023).
Google Scholar
Schenk, A. et al. Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer. Am. J. Physiol. Cell Physiol. 323, C879–C884 (2022).
Google Scholar
Frydelund-Larsen, L. et al. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle: regulation of CXCR2 by exercise. Exp. Physiol. 92, 233–240 (2007).
Google Scholar
Stadtmann, A. & Zarbock, A. CXCR2: from bench to bedside. Front. Immunol. 3, 263 (2012).
Jurcevic, S. et al. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions: effects of CXCR2 antagonism on human neutrophils. Br. J. Clin. Pharmacol. 80, 1324–1336 (2015).
Google Scholar
Hoffman-Goetz, L. & Pedersen, B. K. Exercise and the immune system: a model of the stress response? Immunol. Today 15, 382–387 (1994).
Google Scholar
Pedersen, B. K. Effects of exercise on lymphocytes and cytokines. Br. J. Sports Med. 34, 246–251 (2000).
Google Scholar
Schlagheck, M. L. et al. Cellular immune response to acute exercise: comparison of endurance and resistance exercise. Eur. J. Haematol. 105, 75–84 (2020).
Google Scholar
Peake, J. M., Neubauer, O., Walsh, N. P. & Simpson, R. J. Recovery of the immune system after exercise. J. Appl. Physiol. 122, 1077–1087 (2017).
Google Scholar
Leonard, J. et al. The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications. Immunity. 50, 832–850 (2019).
Straat, M. E. et al. Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue. Cell Rep. Med. 4, 100942 (2023).
Google Scholar
Hansen, J. S. et al. Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio. J. Clin. Endocrinol. Metab. 101, 550–560 (2016).
Google Scholar
Lee, S.-J. et al. Regulation of muscle mass by follistatin and activins. Mol. Endocrinol. 24, 1998–2008 (2010).
Google Scholar
Han, X. et al. Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle. J. Cachexia Sarcopenia Muscle 10, 1241–1257 (2019).
Google Scholar
Winbanks, C. E. et al. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J. Cell Biol. 197, 997–1008 (2012).
Google Scholar
Catoire, M. et al. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise. Proc. Natl. Acad. Sci. 111, E1043–52 (2014).
Norheim, F. et al. Regulation of angiopoietin-like protein 4 production during and after exercise. Physiol. Rep. 2, e12109 (2014).
Google Scholar
Gray, N. E. et al. Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. J. Biol. Chem. 287, 8444–8456 (2012).
Google Scholar
Zhang, H. et al. Aerobic exercise improves endothelial function and serum adropin levels in obese adolescents independent of body weight loss. Sci. Rep. 7, 17717 (2017).
Google Scholar
Fujie, S. et al. Aerobic exercise restores aging‐associated reductions in arterial adropin levels and improves adropin‐induced nitric oxide‐dependent vasorelaxation. J. Am. Heart Assoc. 10, e020641 (2021).
Google Scholar
Parlak, H. et al. Adropin increases with swimming exercise and exerts a protective effect on the brain of aged rats. Exp. Gerontol. 169, 111972 (2022).
Google Scholar
Yang, W. et al. Exercise suppresses NLRP3 inflammasome activation in mice with diet-induced NASH: a plausible role of adropin. Lab. Investig. 101, 369–380 (2021).
Google Scholar
Kuramoto, K., Liang, H., Hong, J.-H. & He, C. Exercise-activated hepatic autophagy via the FN1-α5β1 integrin pathway drives metabolic benefits of exercise. Cell Metab. 35, 620–632.e5 (2023).
Google Scholar
Chen, Y. et al. An acute bout of exercise suppresses appetite via central lactate metabolism. Neuroscience 510, 49–59 (2023).
Google Scholar
Carrière, A. et al. Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. Diabetes 63, 3253–3265 (2014).
Google Scholar
Henstridge, D. C., Febbraio, M. A. & Hargreaves, M. Heat shock proteins and exercise adaptations. Our knowledge thus far and the road still ahead. J. Appl. Physiol. 120, 683–691 (2016).
Google Scholar
Xu, T. et al. HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy. Biochem. Biophys. Res. Commun. 460, 622–627 (2015).
Google Scholar
Archer, A. E., Von Schulze, A. T. & Geiger, P. C. Exercise, heat shock proteins and insulin resistance. Philos. Trans. R. Soc. B Biol. Sci. 373, 20160529 (2018).
Google Scholar
Noble, E. G., Milne, K. J. & Melling, C. W. J. Heat shock proteins and exercise: a primer. Appl. Physiol. Nutr. Metab. 33, 1050–1075 (2008).
Google Scholar
Bei, Y. et al. Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury. Basic Res. Cardiol. 112, 38 (2017).
Google Scholar
Thompson, H. S., Clarkson, P. M. & Scordilis, S. P. The repeated bout effect and heat shock proteins: intramuscular HSP27 and HSP70 expression following two bouts of eccentric exercise in humans. Acta Physiol. Scand. 174, 47–56 (2002).
Google Scholar
Goto, C. et al. Acute moderate-intensity exercise induces vasodilation through an increase in nitric oxide bioavailiability in humans. Am. J. Hypertens. 20, 825–830 (2007).
Google Scholar
Jungersten, L., Ambring, A., Wall, B. & Wennmalm, Å. Both physical fitness and acute exercise regulate nitric oxide formation in healthy humans. J. Appl. Physiol. 82, 760–764 (1997).
Google Scholar
Green, D. J., Maiorana, A., O’Driscoll, G. & Taylor, R. Effect of exercise training on endothelium‐derived nitric oxide function in humans. J. Physiol. 561, 1–25 (2004).
Google Scholar
Hambrecht, R. et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107, 3152–3158 (2003).
Google Scholar
Maiorana, A., O’Driscoll, G., Taylor, R. & Green, D. Exercise and the nitric oxide vasodilator system. Sports Med 33, 1013–1035 (2003).
Google Scholar
Michel, T. & Feron, O. Nitric oxide synthases: which, where, how, and why? J. Clin. Investig. 100, 2146–2152 (1997).
Google Scholar
Song, W., Kwak, H.-B., Kim, J.-H. & Lawler, J. M. Exercise training modulates the nitric oxide synthase profile in skeletal muscle from old rats. J. Gerontol. A. Biol. Sci. Med. Sci. 64A, 540–549 (2009).
Google Scholar
Powers, S. K., Duarte, J., Kavazis, A. N. & Talbert, E. E. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp. Physiol. 95, 1–9 (2010).
Google Scholar
He, F. et al. Redox mechanism of reactive oxygen species in exercise. Front. Physiol. 7, 486 (2016).
Niess, A. M. Response and adaptation of skeletal muscle to exercise—the role of reactive oxygen species. Front. Biosci. 12, 4826 (2007).
Google Scholar
Leiter, O. et al. Selenium mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging. Cell Metab. 34, 408–423.e8 (2022).
Google Scholar
Mulcahy, L. A., Pink, R. C. & Carter, D. R. F. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3, 24641 (2014).
Google Scholar
Iannotta, D., Amruta, A., Kijas, A. W., Rowan, A. E. & Wolfram, J. Entry and exit of extracellular vesicles to and from the blood circulation. Nat. Nanotechnol. 19, 13–20 (2024).
Google Scholar
World Health Organization. Global health estimates 2019: deaths by cause, age, sex, by country and by region, 2000–2019. (2020).
Nocon, M. et al. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur. J. Cardiovasc. Prev. Rehabil. 15, 239–246 (2008).
Google Scholar
Schmid, D. & Leitzmann, M. F. Association between physical activity and mortality among breast cancer and colorectal cancer survivors: a systematic review and meta-analysis. Ann. Oncol. 25, 1293–1311 (2014).
Google Scholar
Boniol, M., Dragomir, M., Autier, P. & Boyle, P. Physical activity and change in fasting glucose and HbA1c: a quantitative meta-analysis of randomized trials. Acta Diabetol. 54, 983–991 (2017).
Google Scholar
Jadhav, R. A., Hazari, A., Monterio, A., Kumar, S. & Maiya, A. G. Effect of physical activity intervention in prediabetes: a systematic review with meta-analysis. J. Phys. Act. Health 14, 745–755 (2017).
Google Scholar
Stewart, R. A. H. et al. Physical activity and mortality in patients with stable coronary heart disease. J. Am. Coll. Cardiol. 70, 1689–1700 (2017).
Google Scholar
Waschki, B. et al. Physical activity is the strongest predictor of all-cause mortality in patients With COPD. Chest 140, 331–342 (2011).
Google Scholar
Wen, C. et al. Pre‐stroke physical activity is associated with fewer post‐stroke complications, lower mortality and a better long‐term outcome. Eur. J. Neurol. 24, 1525–1531 (2017).
Google Scholar
Bull, F. C. et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br. J. Sports Med. 54, 1451–1462 (2020).
Google Scholar
Global action plan on physical activity 2018–2030: more active people for a healthier world. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789241514187.
Fiuza-Luces, C., Garatachea, N., Berger, N. A. & Lucia, A. Exercise is the real polypill. Physiology 28, 330–358 (2013).
Google Scholar
Pareja-Galeano, H., Garatachea, N. & Lucia, A. Exercise as a polypill for chronic diseases. in Progress in Molecular Biology and Translational Science (ed. Bouchard, C.) vol. 135 497–526 (Academic Press, 2015).
Ho, M. et al. Impact of dietary and exercise interventions on weight change and metabolic outcomes in obese children and adolescents: a systematic review and meta-analysis of randomized trials. JAMA Pediatr. 167, 759 (2013).
Google Scholar
Miller, W., Koceja, D. & Hamilton, E. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. Int. J. Obes. 21, 941–947 (1997).
Google Scholar
Stoner, L. et al. Efficacy of exercise intervention for weight loss in overweight and obese adolescents: meta-analysis and implications. Sports Med 46, 1737–1751 (2016).
Google Scholar
Huang, L., Fang, Y. & Tang, L. Comparisons of different exercise interventions on glycemic control and insulin resistance in prediabetes: a network meta-analysis. BMC Endocr. Disord. 21, 181 (2021).
Google Scholar
Bonfante, I. L. P. et al. Combined training increases thermogenic fat activity in patients with overweight and type 2 diabetes. Int. J. Obes. 46, 1145–1154 (2022).
Google Scholar
Martinez-Tellez, B. et al. No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial. Nat. Commun. 13, 5259 (2022).
Google Scholar
Willis, L. H. et al. Effects of aerobic and/or resistance training on body mass and fat mass in overweight or obese adults. J. Appl. Physiol. 113, 1831–1837 (2012).
Google Scholar
Chew, N. W. S. et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab. 35, 414–428.e3 (2023).
Google Scholar
Gourdy, P. et al. Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic‐euglycaemic clamp. Diabetes Obes. Metab. 20, 157–164 (2018).
Google Scholar
Geng, L., Lam, K. S. L. & Xu, A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat. Rev. Endocrinol. 16, 654–667 (2020).
Google Scholar
Shao, W. & Jin, T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis. Transl. Med. 8, 19–25 (2022).
Google Scholar
Carey, A. L. et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006).
Google Scholar
Amaral, S. L., Papanek, P. E. & Greene, A. S. Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training. Am. J. Physiol. Heart Circ. Physiol. 281, H1163–H1169 (2001).
Google Scholar
Lu, X. et al. Effect and mechanism of intermittent myocardial ischemia induced by exercise on coronary collateral formation. Am. J. Phys. Med. Rehabil. 87, 803–814 (2008).
Google Scholar
Wu, G. et al. Exercise-induced expression of VEGF and salvation of myocardium in the early stage of myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 296, H389–H395 (2009).
Google Scholar
Moien-Afshari, F. et al. Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice. Diabetologia 51, 1327–1337 (2008).
Google Scholar
Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018).
Google Scholar
Cornelissen, V. A. & Smart, N. A. Exercise training for blood pressure: a systematic review and meta‐analysis. J. Am. Heart Assoc. 2, e004473 (2013).
Google Scholar
De Sousa, E. C. et al. Resistance training alone reduces systolic and diastolic blood pressure in prehypertensive and hypertensive individuals: meta-analysis. Hypertens. Res. 40, 927–931 (2017).
Google Scholar
Whelton, S. P., Chin, A., Xin, X. & He, J. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann. Intern. Med. 136, 493 (2002).
Google Scholar
Blumenthal, J. A. et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure. Arch. Intern. Med. 170, 126–135 (2010).
Ostman, C. et al. The effect of exercise training on clinical outcomes in patients with the metabolic syndrome: a systematic review and meta-analysis. Cardiovasc. Diabetol. 16, 110 (2017).
Google Scholar
Jhamnani, S. et al. Meta-analysis of the effects of lifestyle modifications on coronary and carotid atherosclerotic burden. Am. J. Cardiol. 115, 268–275 (2015).
Google Scholar
Davignon, J. & Ganz, P. Role of endothelial dysfunction in atherosclerosis. Circulation 109, III27–32 (2004).
Ashor, A. W. et al. Exercise modalities and endothelial function: a systematic review and dose–response meta-analysis of randomized controlled trials. Sports Med. 45, 279–296 (2015).
Google Scholar
Lawler, P. R., Filion, K. B. & Eisenberg, M. J. Efficacy of exercise-based cardiac rehabilitation post–myocardial infarction: a systematic review and meta-analysis of randomized controlled trials. Am. Heart J. 162, 571–584.e2 (2011).
Google Scholar
ExTraMATCH Collaborative. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 328, 189–0 (2004).
Google Scholar
Taylor, R. et al. Exercise‐based rehabilitation for heart failure. Cochrane Database Syst. Rev. 2014, CD003331 (2014).
Cornelis, J., Beckers, P., Taeymans, J., Vrints, C. & Vissers, D. Comparing exercise training modalities in heart failure: a systematic review and meta-analysis. Int. J. Cardiol. 221, 867–876 (2016).
Google Scholar
Moreira, J. B. N. et al. Exercise reveals proline dehydrogenase as a potential target in heart failure. Prog. Cardiovasc. Dis. 62, 193–202 (2019).
Google Scholar
Goto, C. et al. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress. Circulation 108, 530–535 (2003).
Google Scholar
Higashi, Y. et al. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation 100, 1194–1202 (1999).
Google Scholar
Brame, A. L. et al. Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension 65, 834–840 (2015).
Google Scholar
Japp, A. G. et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 121, 1818–1827 (2010).
Google Scholar
Amadio, P. et al. Patho- physiological role of BDNF in fibrin clotting. Sci. Rep. 9, 389 (2019).
Google Scholar
Yuan, R. et al. Vascular endothelial growth factor gene transfer therapy for coronary artery disease: a systematic review and meta‐analysis. Cardiovasc. Ther. 36, e12461 (2018).
Google Scholar
Ferrara, N., Hillan, K. J., Gerber, H.-P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).
Google Scholar
Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat. Clin. Pract. Oncol. 3, 24–40 (2006).
Google Scholar
Jabbour, A. et al. Parenteral administration of recombinant human neuregulin‐1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur. J. Heart Fail. 13, 83–92 (2011).
Google Scholar
Lenihan, D. J. et al. A phase I, single ascending dose study of cimaglermin alfa (Neuregulin 1β3) in patients with systolic dysfunction and heart failure. JACC Basic Transl. Sci. 1, 576–586 (2016).
Google Scholar
Winkle, P. et al. A first-in-human study of AMG 986, a novel apelin receptor agonist, in healthy subjects and heart failure patients. Cardiovasc. Drugs Ther. 37, 743–755 (2023).
Google Scholar
Fontes, J. A., Rose, N. R. & Čiháková, D. The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine 74, 62–68 (2015).
Google Scholar
Steffl, M. et al. Relationship between sarcopenia and physical activity in older people: a systematic review and meta-analysis. Clin. Interv. Aging 12, 835–845 (2017).
Google Scholar
Beckwée, D. et al. Exercise interventions for the prevention and treatment of sarcopenia. a systematic umbrella review. J. Nutr. Health Aging 23, 494–502 (2019).
Google Scholar
Vlietstra, L., Hendrickx, W. & Waters, D. L. Exercise interventions in healthy older adults with sarcopenia: a systematic review and meta‐analysis. Australas. J. Ageing 37, 169–183 (2018).
Google Scholar
Alves, C. R. R. et al. Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN. Mol. Metab. 39, 101012 (2020).
Google Scholar
Ni, H.-J. et al. Effects of Exercise Programs in older adults with Muscle Wasting: A Systematic Review and Meta-analysis. Arch. Gerontol. Geriatr. 99, 104605 (2022).
Google Scholar
Marques, E. A., Mota, J. & Carvalho, J. Exercise effects on bone mineral density in older adults: a meta-analysis of randomized controlled trials. AGE 34, 1493–1515 (2012).
Google Scholar
Wolff, I., Van Croonenborg, J. J., Kemper, H. C. G., Kostense, P. J. & Twisk, J. W. R. The effect of exercise training programs on bone mass: a meta-analysis of published controlled trials in pre- and postmenopausal women. Osteoporos. Int. 9, 1–12 (1999).
Google Scholar
Zhang, S. et al. Effect of exercise on bone mineral density among patients with osteoporosis and osteopenia: a systematic review and network meta‐analysis. J. Clin. Nurs. 31, 2100–2111 (2022).
Google Scholar
Gianola, S. et al. Effect of muscular exercise on patients with muscular dystrophy: a systematic review and meta-analysis of the literature. Front. Neurol. 11, 958 (2020).
Google Scholar
Hammer, S. et al. Exercise training in duchenne muscular dystrophy: a systematic review and meta-analysis. J. Rehabil. Med. 54, jrm00250 (2022).
Google Scholar
Mendell, J. R. et al. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol. Ther. 23, 192–201 (2015).
Google Scholar
Kanzleiter, T. et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem. Biophys. Res. Commun. 450, 1089–1094 (2014).
Google Scholar
Colaianni, G. et al. Irisin and bone: from preclinical studies to the evaluation of its circulating levels in different populations of human subjects. Cells 8, 451 (2019).
Google Scholar
Colaianni, G. et al. Irisin correlates positively with BMD in a cohort of older adult patients and downregulates the senescent marker p21 in osteoblasts. J. Bone Miner. Res. 36, 305–314 (2021).
Google Scholar
Zhou, K., Qiao, X., Cai, Y., Li, A. & Shan, D. Lower circulating irisin in middle-aged and older adults with osteoporosis: a systematic review and meta-analysis. Menopause 26, 1302–1310 (2019).
Google Scholar
Lyssikatos, C. et al. l-β-aminoisobutyric acid, L-BAIBA, a marker of bone mineral density and body mass index, and D-BAIBA of physical performance and age. Sci. Rep. 13, 17212 (2023).
Google Scholar
Wang, Z. et al. Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis. Commun. Biol. 3, 39 (2020).
Google Scholar
Falck, R. S., Davis, J. C., Best, J. R., Crockett, R. A. & Liu-Ambrose, T. Impact of exercise training on physical and cognitive function among older adults: a systematic review and meta-analysis. Neurobiol. Aging 79, 119–130 (2019).
Google Scholar
Northey, J. M., Cherbuin, N., Pumpa, K. L., Smee, D. J. & Rattray, B. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis. Br. J. Sports Med. 52, 154–160 (2018).
Google Scholar
Heyn, P., Abreu, B. C. & Ottenbacher, K. J. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch. Phys. Med. Rehabil. 85, 1694–1704 (2004).
Google Scholar
Jia, R., Liang, J., Xu, Y. & Wang, Y. Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: a meta-analysis. BMC Geriatr. 19, 181 (2019).
Google Scholar
Kim, R. et al. Effects of physical exercise interventions on cognitive function in Parkinson’s disease: an updated systematic review and meta-analysis of randomized controlled trials. Parkinson. Relat. Disord. 117, 105908 (2023).
Google Scholar
Kwakkel, G. et al. Effects of augmented exercise therapy time after stroke: a meta-analysis. Stroke 35, 2529–2539 (2004).
Google Scholar
Stoller, O., De Bruin, E. D., Knols, R. H. & Hunt, K. J. Effects of cardiovascular exercise early after stroke: systematic review and meta-analysis. BMC Neurol. 12, 45 (2012).
Google Scholar
Hou, L. et al. Association between physical exercise and stroke recurrence among first-ever ischemic stroke survivors. Sci. Rep. 11, 13372 (2021).
Google Scholar
Veldema, J. & Jansen, P. Ergometer training in stroke rehabilitation: systematic review and meta-analysis. Arch. Phys. Med. Rehabil. 101, 674–689 (2020).
Google Scholar
Veldema, J. & Jansen, P. Resistance training in stroke rehabilitation: systematic review and meta-analysis. Clin. Rehabil. 34, 1173–1197 (2020).
Google Scholar
Kim, K. Y. et al. Loss of association between plasma irisin levels and cognition in Alzheimer’s disease. Psychoneuroendocrinology 136, 105624 (2022).
Google Scholar
Lourenco, M. V. et al. Cerebrospinal fluid irisin correlates with amyloid‐β, BDNF, and cognition in Alzheimer’s disease. Alzheimers Dement. Diagn. Assess. Dis. Monit. 12, e12034 (2020).
Zhang, X. et al. Irisin exhibits neuroprotection by preventing mitochondrial damage in Parkinson’s disease. Npj Park. Dis. 9, 13 (2023).
Google Scholar
Moxon, J. V. et al. The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: a meta-analysis. J. Cereb. Blood Flow. Metab. 39, 2343–2354 (2019).
Google Scholar
Venkat, P. et al. Treatment with an angiopoietin‐1 mimetic peptide promotes neurological recovery after stroke in diabetic rats. CNS Neurosci. Ther. 27, 48–59 (2021).
Google Scholar
Golledge, J. et al. Plasma angiopoietin-1 is lower after ischemic stroke and associated with major disability but not stroke incidence. Stroke 45, 1064–1068 (2014).
Google Scholar
Huuha, A. M. et al. Can exercise training teach us how to treat Alzheimer’s disease? Ageing Res. Rev. 75, 101559 (2022).
Google Scholar
Tari, A. R. et al. Are the neuroprotective effects of exercise training systemically mediated? Prog. Cardiovasc. Dis. 62, 94–101 (2019).
Google Scholar
Kim, T.-W., Park, S.-S., Park, J.-Y. & Park, H.-S. Infusion of plasma from exercised mice ameliorates cognitive dysfunction by increasing hippocampal neuroplasticity and mitochondrial functions in 3xTg-AD mice. Int. J. Mol. Sci. 21, 3291 (2020).
Google Scholar
Tari, A. R. et al. Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer’s disease: protocol for the ExPlas study. BMJ Open 12, e056964 (2022).
Google Scholar
Sha, S. J. et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for alzheimer symptom amelioration study: a randomized clinical trial. JAMA Neurol. 76, 35 (2019).
Google Scholar
Kurz, E. et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 40, 720–737.e5 (2022).
Google Scholar
San-Millán, I. & Brooks, G. A. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis 38, 119–133 (2017).
Google Scholar
Morrell, M. B. G. et al. Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma. Pediatr. Blood Cancer 66, e27835 (2019).
Google Scholar
Schadler, K. L. et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7, 65429–65440 (2016).
Google Scholar
Pedersen, L., Christensen, J. F. & Hojman, P. Effects of exercise on tumor physiology and metabolism. Cancer J. 21, 111–116 (2015).
Google Scholar
Ruiz-Casado, A. et al. Exercise and the hallmarks of cancer. Trends Cancer 3, 423–441 (2017).
Google Scholar
Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816 (2016).
Google Scholar
Patel, A. V. et al. American College of Sports Medicine roundtable report on physical activity, sedentary behavior, and cancer prevention and control. Med. Sci. Sports Exerc. 51, 2391–2402 (2019).
Google Scholar
Velthuis, M. J., Agasi-Idenburg, S. C., Aufdemkampe, G. & Wittink, H. M. The effect of physical exercise on cancer-related fatigue during cancer treatment: a meta-analysis of randomised controlled trials. Clin. Oncol. 22, 208–221 (2010).
Google Scholar
Scott, J. M. et al. Efficacy of exercise therapy on cardiorespiratory fitness in patients with cancer: a systematic review and meta-analysis. J. Clin. Oncol. 36, 2297–2305 (2018).
Google Scholar
Betof, A. S., Dewhirst, M. W. & Jones, L. W. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain. Behav. Immun. 30, S75–S87 (2013).
Google Scholar
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9, 34 (2017).
Google Scholar
Emery, A., Moore, S., Turner, J. E. & Campbell, J. P. Reframing how physical activity reduces the incidence of clinically-diagnosed cancers: appraising exercise-induced immuno-modulation as an integral mechanism. Front. Oncol. 12, 788113 (2022).
Google Scholar
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Google Scholar
Niccoli, T. & Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 22, R741–R752 (2012).
Google Scholar
Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).
Google Scholar
Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).
Google Scholar
López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L. & Kroemer, G. Meta-hallmarks of aging and cancer. Cell Metab. 35, 12–35 (2023).
Google Scholar
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).
Google Scholar
Schmauck-Medina, T. et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging 14, 6829–6839 (2022).
Google Scholar
Garatachea, N. et al. Exercise attenuates the major hallmarks of aging. Rejuvenation Res. 18, 57–89 (2015).
Google Scholar
Horowitz, A. M. & Villeda, S. A. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease. F1000Research 6, 1291 (2017).
Google Scholar
Bouchard, J. & Villeda, S. A. Aging and brain rejuvenation as systemic events. J. Neurochem. 132, 5–19 (2015).
Google Scholar
Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).
Google Scholar
Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).
Google Scholar
Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).
Google Scholar
Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014).
Google Scholar
Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).
Google Scholar
Ho, T. T. et al. Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions. J. Exp. Med. 218, e20210223 (2021).
Google Scholar
Van Praag, H., Shubert, T., Zhao, C. & Gage, F. H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685 (2005).
Google Scholar
Firth, J. et al. Effect of aerobic exercise on hippocampal volume in humans: a systematic review and meta-analysis. NeuroImage 166, 230–238 (2018).
Google Scholar
Sofi, F. et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies: physical activity and risk of cognitive decline. J. Intern. Med. 269, 107–117 (2011).
Google Scholar
Chang, Y. K., Labban, J. D., Gapin, J. I. & Etnier, J. L. The effects of acute exercise on cognitive performance: a meta-analysis. Brain Res. 1453, 87–101 (2012).
Google Scholar
Leiter, O. & Walker, T. L. Platelets: the missing link between the blood and brain? Prog. Neurobiol. 183, 101695 (2019).
Google Scholar
Burnouf, T. & Walker, T. L. The multifaceted role of platelets in mediating brain function. Blood 140, 815–827 (2022).
Google Scholar
Bieri, G., Schroer, A. B. & Villeda, S. A. Blood-to-brain communication in aging and rejuvenation. Nat. Neurosci. 26, 379–393 (2023).
Google Scholar
Brunet, A., Goodell, M. A. & Rando, T. A. Ageing and rejuvenation of tissue stem cells and their niches. Nat. Rev. Mol. Cell Biol. 24, 45–62 (2023).
Google Scholar
Vargason, A. M., Anselmo, A. C. & Mitragotri, S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 5, 951–967 (2021).
Google Scholar
Dollet, L. et al. Exercise-induced crosstalk between immune cells and adipocytes in humans: role of oncostatin-M. Cell Rep. Med. 5, 101348 (2024).
Google Scholar
Wei, W., Raun, S. H. & Long, J. Z. Molecular insights from multiomics studies of physical activity. Diabetes 73, 162–168 (2024).
Google Scholar
Mittenbühler, M. J. et al. Isolation of extracellular fluids reveals novel secreted bioactive proteins from muscle and fat tissues. Cell Metab. 35, 535–549.e7 (2023).
Google Scholar
Trappe, T. et al. Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach. J. Physiol. 554, 803–813 (2004).
Google Scholar
Sanford, J. A. et al. Molecular Transducers of Physical Activity Consortium (MoTrPAC): mapping the dynamic responses to exercise. Cell 181, 1464–1474 (2020).
Google Scholar
Noone, J., Mucinski, J. M., DeLany, J. P., Sparks, L. M. & Goodpaster, B. H. Understanding the variation in exercise responses to guide personalized physical activity prescriptions. Cell Metab. 36, 702–724 (2024).
Google Scholar
Tanimura, Y. et al. Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Physiol. Rep. 4, e12828 (2016).
Zhang, H. et al. GDF15 mediates the effect of skeletal muscle contraction on glucose-stimulated insulin secretion. Diabetes 72, 1070–1082 (2023).
Google Scholar
Pedersen, B. K., Steensberg, A. & Schjerling, P. Muscle‐derived interleukin‐6: possible biological effects. J. Physiol. 536, 329–337 (2001).
Google Scholar
Steensberg, A. et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. 529, 237–242 (2000).
Google Scholar
Haugen, F. et al. IL-7 is expressed and secreted by human skeletal muscle cells. Am. J. Physiol. Cell Physiol. 298, C807–C816 (2010).
Google Scholar
Pedersen, B. K. Muscles and their myokines. J. Exp. Biol. 214, 337–346 (2011).
Google Scholar
Nishizawa, H. et al. Musclin, a novel skeletal muscle-derived secretory factor. J. Biol. Chem. 279, 19391–19395 (2004).
Google Scholar
Pourranjbar, M. et al. Effects of aerobic exercises on serum levels of myonectin and insulin resistance in obese and overweight women. J. Med. Life 11, 381–386 (2018).
Google Scholar
Arsic, N. et al. Vascular endothelial growth factor stimulates skeletal muscle regeneration in Vivo. Mol. Ther. 10, 844–854 (2004).
Google Scholar
Birot, O. J. G., Koulmann, N., Peinnequin, A. & Bigard, X. A. Exercise‐induced expression of vascular endothelial growth factor mRNA in rat skeletal muscle is dependent on fibre type. J. Physiol. 552, 213–221 (2003).
Google Scholar
Hoier, B. et al. Pro‐ and anti‐angiogenic factors in human skeletal muscle in response to acute exercise and training. J. Physiol. 590, 595–606 (2012).
Google Scholar
Gavin, T. P. et al. Angiogenic growth factor response to acute systemic exercise in human skeletal muscle. J. Appl. Physiol. 96, 19–24 (2004).
Google Scholar
Kraus, R. M., Stallings, H. W., Yeager, R. C. & Gavin, T. P. Circulating plasma VEGF response to exercise in sedentary and endurance-trained men. J. Appl. Physiol. 96, 1445–1450 (2004).
Google Scholar
Perakakis, N. et al. Physiology of activins/follistatins: associations with metabolic and anthropometric variables and response to exercise. J. Clin. Endocrinol. Metab. 103, 3890–3899 (2018).
Google Scholar
Hansen, J. et al. Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. Endocrinology 152, 164–171 (2011).
Google Scholar
Khalafi, M., Aria, B., Symonds, M. E. & Rosenkranz, S. K. The effects of resistance training on myostatin and follistatin in adults: a systematic review and meta-analysis. Physiol. Behav. 269, 114272 (2023).
Google Scholar
Xi, Y., Gong, D.-W. & Tian, Z. FSTL1 as a potential mediator of exercise-induced cardioprotection in post-myocardial infarction rats. Sci. Rep. 6, 32424 (2016).
Google Scholar
Görgens, S. W. et al. Regulation of follistatin-like protein 1 expression and secretion in primary human skeletal muscle cells. Arch. Physiol. Biochem. 119, 75–80 (2013).
Google Scholar
Strömberg, A. et al. CX 3 CL1—a macrophage chemoattractant induced by a single bout of exercise in human skeletal muscle. Am. J. Physiol. -Regul. Integr. Comp. Physiol. 310, R297–R304 (2016).
Google Scholar
Reza, M. M. et al. Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Nat. Commun. 8, 1104 (2017).
Google Scholar
Roca-Rivada, A. et al. FNDC5/Irisin is not only a myokine but also an adipokine. PLoS One 8, e60563 (2013).
Google Scholar
Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 19, 302–309 (2014).
Google Scholar
Christiansen, T. et al. Diet-induced weight loss and exercise alone and in combination enhance the expression of adiponectin receptors in adipose tissue and skeletal muscle, but only diet-induced weight loss enhanced circulating adiponectin. J. Clin. Endocrinol. Metab. 95, 911–919 (2010).
Google Scholar
Lim, S. et al. Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women. J. Clin. Endocrinol. Metab. 93, 2263–2268 (2008).
Google Scholar
Kriketos, A. D. et al. Exercise increases adiponectin levels and insulin sensitivity in humans. Diabetes Care 27, 629–630 (2004).
Google Scholar
Boucher, J. et al. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 146, 1764–1771 (2005).
Google Scholar
Besse-Patin, A. et al. Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine. Int. J. Obes. 38, 707–713 (2014).
Google Scholar
Bae, J. Y. Aerobic exercise increases meteorin-like protein in muscle and adipose tissue of chronic high-fat diet-induced obese mice. BioMed. Res. Int. 2018, 1–8 (2018).
Feng, L. et al. Exercise training protects against heart failure via expansion of myeloid-derived suppressor cells through regulating IL-10/STAT3/S100A9 pathway. Circ. Heart Fail. 15, e008550 (2022).
Google Scholar
Cabral‐Santos, C. et al. Interleukin‐10 responses from acute exercise in healthy subjects: a systematic review. J. Cell. Physiol. 234, 9956–9965 (2019).
Google Scholar
Steensberg, A., Fischer, C. P., Keller, C., Møller, K. & Pedersen, B. K. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol. Endocrinol. Metab. 285, E433–E437 (2003).
Google Scholar
Nieman, D. C. et al. Blood leukocyte mRNA expression for IL-10, IL-1Ra, and IL-8, but Not IL-6, increases after exercise. J. Interferon Cytokine Res. 26, 668–674 (2006).
Google Scholar
Pedersen, B. K., Steensberg, A. & Schjerling, P. Exercise and interleukin-6. Curr. Opin. Hematol. 8, 137–141 (2001).
Google Scholar
Neves, R. V. P. et al. Dynamic not isometric training blunts osteo-renal disease and improves the sclerostin/FGF23/Klotho axis in maintenance hemodialysis patients: a randomized clinical trial. J. Appl. Physiol. 130, 508–516 (2021).
Google Scholar
Lee, S., Kolset, S. O., Birkeland, K. I., Drevon, C. A. & Reine, T. M. Acute exercise increases syndecan-1 and -4 serum concentrations. Glycoconj. J. 36, 113–125 (2019).
Google Scholar
Choi, S. H. et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821 (2018).
Google Scholar
Griffin, É. W. et al. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol. Behav. 104, 934–941 (2011).
Google Scholar
Mohammadzadeh, R. et al. Association of neuregulin-1β with physiological cardiac hypertrophy following acute and chronic exercise in athlete and non-athlete women. Hum. Physiol. 48, 102–107 (2022).
Google Scholar
Bugera, E. M., Duhamel, T. A., Peeler, J. D. & Cornish, S. M. The systemic myokine response of decorin, interleukin-6 (IL-6) and interleukin-15 (IL-15) to an acute bout of blood flow restricted exercise. Eur. J. Appl. Physiol. 118, 2679–2686 (2018).
Google Scholar
Jane, D. T. et al. Evidence for the involvement of cathepsin B in skeletal myoblast differentiation. J. Cell. Biochem. 84, 520–531 (2002).
Google Scholar
Jurrissen, T. J. et al. Role of adropin in arterial stiffening associated with obesity and type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol. 323, H879–H891 (2022).
Google Scholar
Fujie, S. et al. Aerobic exercise training-induced changes in serum adropin level are associated with reduced arterial stiffness in middle-aged and older adults. Am. J. Physiol. Heart Circ. Physiol. 309, H1642–H1647 (2015).
Google Scholar
Wei, J. et al. Physical exercise modulates the microglial complement pathway in mice to relieve cortical circuitry deficits induced by mutant human TDP-43. Cell Rep. 42, 112240 (2023).
Google Scholar
Campisi, J. et al. Habitual physical activity facilitates stress-induced HSP72 induction in brain, peripheral, and immune tissues. Am. J. Physiol. -Regul. Integr. Comp. Physiol. 284, R520–R530 (2003).
Google Scholar
Morton, J. P., Kayani, A. C., McArdle, A. & Drust, B. The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Med. 39, 643–662 (2009).
Google Scholar
Joisten, N. et al. Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training. Exerc. Immunol. Rev. 20, 24–42 (2020).
Elrod, J. W., Calvert, J. W., Gundewar, S., Bryan, N. S. & Lefer, D. J. Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide. Proc. Natl Acad. Sci. 105, 11430–11435 (2008).
Google Scholar
Sahlin, K. et al. Ultraendurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle. J. Appl. Physiol. 108, 780–787 (2010).
Google Scholar
Rogers, P. J. et al. Catecholamine metabolic pathways and exercise training. Plasma and urine catecholamines, metabolic enzymes, and chromogranin-A. Circulation 84, 2346–2356 (1991).
Google Scholar
Jorfeldt, L., Juhlin-Dannfelt, A. & Karlsson, J. Lactate release in relation to tissue lactate in human skeletal muscle during exercise. J. Appl. Physiol. 44, 350–352 (1978).
Google Scholar
Siqueira, I. R., Palazzo, R. P. & Cechinel, L. R. Circulating extracellular vesicles delivering beneficial cargo as key players in exercise effects. Free Radic. Biol. Med. 172, 273–285 (2021).
Google Scholar
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).
Google Scholar
Baggish, A. L. et al. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J. Physiol. 589, 3983–3994 (2011).
Google Scholar
Chen, J. et al. Aerobic exercise suppresses cognitive injury in patients with Alzheimer’s disease by regulating long non-coding RNA TUG1. Neurosci. Lett. 826, 137732 (2024).
Google Scholar
Cai, T.-Q. et al. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem. Biophys. Res. Commun. 377, 987–991 (2008).
Google Scholar
Liu, C. et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284, 2811–2822 (2009).
Google Scholar
Henstridge, D. C. et al. Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes 63, 1881–1894 (2014).
Google Scholar
Park, H.-S. Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J. 20, 446–456 (2001).
Google Scholar
Parcellier, A. et al. HSP27 is a ubiquitin-binding protein involved in i-Kbα proteasomal degradation. Mol. Cell. Biol. 23, 5790–5802 (2003).
Google Scholar
Park, K.-J., Gaynor, R. B. & Kwak, Y. T. Heat shock protein 27 association with the iκb kinase complex regulates tumor necrosis factor α-induced NF-κB activation. J. Biol. Chem. 278, 35272–35278 (2003).
Google Scholar
Francis, S. H., Busch, J. L. & Corbin, J. D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol. Rev. 62, 525–563 (2010).
Google Scholar
Kojda, G., Cheng, Y. C., Burchfield, J. & Harrison, D. G. Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103, 2839–2844 (2001).
Google Scholar
Van Meijel, L. A. et al. Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes. BMJ Open Diabetes Res. Care 10, e002401 (2022).
Google Scholar
Charles, E. D. et al. Pegbelfermin (BMS‐986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity 27, 41–49 (2019).
Google Scholar
Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016).
Google Scholar
Kim, A. M. et al. Once‐weekly administration of a long‐acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non‐human primates. Diabetes Obes. Metab. 19, 1762–1772 (2017).
Google Scholar
Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013).
Google Scholar
Parry-Jones, A. R. et al. Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH). Eur. Stroke J. 8, 819–827 (2023).
Google Scholar
Shi, C.-X. et al. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes. Sci. Rep. 6, 21924 (2016).
Google Scholar
Klein, A. B. et al. Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nat. Commun. 12, 1041 (2021).
Google Scholar
link
