Caspersen, C. J. & Christenson, P. G. M. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 100, 126–131 (1985).
Garber, C. E. et al. American college of sports medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med. Sci. Sports Exerc 43, 1334–1359 (2011).
Arem, H. et al. Leisure time physical activity and mortality. JAMA Intern. Med. 175, 959–967 (2015).
Bauman, A. E. et al. An evidence-based assessment of the impact of the Olympic Games on population levels of physical activity. Lancet 398, 456–464 (2021).
Lieberman, D. E., Kistner, T. M., Richard, D., Lee, I. & Baggish, A. L. The active grandparent hypothesis: physical activity and the evolution of extended human healthspans and lifespans. Proc. Natl Acad. Sci. USA 118, e2107621118 (2021).
Kohl, H. W. et al. The pandemic of physical inactivity: global action for public health. Lancet 380, 294–305 (2012).
Bull, F. C. et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br. J. Sports Med. 54, 1451–1462 (2020).
Hallal, P. C. et al. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet 380, 247–257 (2012).
Lavie, C. J., Ozemek, C., Carbone, S., Katzmarzyk, P. T. & Blair, S. N. Sedentary behavior, exercise, and cardiovascular health. Circ. Res. 124, 799–815 (2019).
Lee, C., Han, K., Yoo, J. & Kwak, M. Synergistic harmful interaction between sustained physical inactivity and hypertension/diabetes mellitus on the risk of all-cause mortality: a retrospective observational cohort study. J. Hypertens. 39, 2058–2066 (2021).
Medina, C. et al. Cardiovascular and diabetes burden attributable to physical inactivity in Mexico. Cardiovasc. Diabetol. 19, 99 (2020).
Patterson, R. et al. Sedentary behaviour and risk of all-cause, cardiovascular and cancer mortality, and incident type 2 diabetes: a systematic review and dose response meta-analysis. Eur. J. Epidemiol. 33, 811–829 (2018).
Lee, I. 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).
Rodriguez-Ayllon, M. et al. Role of physical activity and sedentary behavior in the mental health of preschoolers, children and adolescents: a systematic review and meta-analysis. Sports Med. 49, 1383–1410 (2019).
Kandola, A., Ashdown-Franks, G., Hendrikse, J., Sabiston, C. M. & Stubbs, B. Physical activity and depression: towards understanding the antidepressant mechanisms of physical activity. Neurosci. Biobehav. Rev. 107, 525–539 (2019).
Nooijen, C., Blom, V., Ekblom, O., Ekblom, M. M. & Kallings, L. V. Improving office workers’ mental health and cognition: a 3-arm cluster randomized controlled trial targeting physical activity and sedentary behavior in multi-component interventions. BMC Public Health 19, 266 (2019).
Erguson, B. F. ACSM’s guidelines for exercise testing and prescription 9th Ed. 2014. J. Can. Chiropr. Assoc. 58, 328 (2014).
Lamberti, N. et al. Effects of low-intensity endurance and resistance training on mobility in chronic stroke survivors: a pilot randomized controlled study. Eur. J. Phys. Rehab. Med. 53, 228–239 (2017).
Wehrle, A., Kneis, S., Dickhuth, H., Gollhofer, A. & Bertz, H. Endurance and resistance training in patients with acute leukemia undergoing induction chemotherapy—a randomized pilot study. Support. Care Cancer 27, 1071–1079 (2019).
Garcia-Pinillos, F., Laredo-Aguilera, J. A., Munoz-Jimenez, M. & Latorre-Roman, P. A. Effects of 12-week concurrent high-intensity interval strength and endurance training program on physical performance in healthy older people. J. Strength Cond. Res. 33, 1445–1452 (2019).
Gibala, M. J., Little, J. P., MacDonald, M. J. & Hawley, J. A. Physiological adaptations to low-volume, high-intensity interval training in health and disease. J. Physiol. 590, 1077–1084 (2012).
Knuiman, P., Hopman, M. T. E. & Mensink, M. Glycogen availability and skeletal muscle adaptations with endurance and resistance exercise. Nutr. Metab. 12, 59 (2015).
Gabriele et al. Muscle stem cell and physical activity: what point is the debate at? Open Med. 12, 144–156 (2017).
Folland, J. P. & Williams, A. G. The adaptations to strength training: morphological and neurological contributions to increased strength. Sports Med. 37, 145–168 (2007).
Hoppeler, H., Baum, O., Lurman, G. & Mueller, M. Molecular mechanisms of muscle plasticity with exercise. Compr. Physiol. 1, 1383–1412 (2011).
Farup, J., Sørensen, H. & Kjølhede, T. Similar changes in muscle fiber phenotype with differentiated consequences for rate of force development: endurance versus resistance training. Hum. Mov. Sci. 34, 109–119 (2014).
McGee, S. L. & Hargreaves, M. Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit. Nat. Rev. Endocrinol. 16, 495–505 (2020).
Garber, C. E. et al. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults. Med. Sci. Sports Exerc. 43, 1334–1359 (2011).
Wilder, R. P. et al. Physical fitness assessment: an update. J. Long. Term. Eff. Med. Implants 16, 193–204 (2006).
Swift, D. L., Johannsen, N. M., Lavie, C. J., Earnest, C. P. & Church, T. S. The role of exercise and physical activity in weight loss and maintenance. Prog. Cardiovasc. Dis. 56, 441–447 (2014).
Androulakis-Korakakis, P., Fisher, J. P. & Steele, J. The minimum effective training dose required to increase 1RM strength in resistance-trained men: a systematic review and meta-analysis. Sports Med. 50, 751–765 (2020).
Martin-Smith, R. et al. High intensity interval training (HIIT) improves cardiorespiratory fitness (CRF) in healthy, overweight and obese adolescents: a systematic review and meta-analysis of controlled studies. Int. J. Environ. Res. Public Health 17, 2955 (2020).
CHIN, E. C. et al. Low-frequency HIIT improves body composition and aerobic capacity in overweight men. Med. Sci. Sports Exerc. 52, 56–66 (2020).
Grace, F. et al. High intensity interval training (HIIT) improves resting blood pressure, metabolic (MET) capacity and heart rate reserve without compromising cardiac function in sedentary aging men. Exp. Gerontol. 109, 75–81 (2018).
Su, L. et al. Effects of HIIT and MICT on cardiovascular risk factors in adults with overweight and/or obesity: a meta-analysis. PLoS ONE 14, e210644 (2019).
Wewege, M., van den Berg, R., Ward, R. E. & Keech, A. The effects of high-intensity interval training vs. moderate-intensity continuous training on body composition in overweight and obese adults: a systematic review and meta-analysis. Obes. Rev. 18, 635–646 (2017).
Ross, L. M., Porter, R. R. & Durstine, J. L. High-intensity interval training (HIIT) for patients with chronic diseases. J. Sport Health Sci. 5, 139–144 (2016).
Fiuza-Luces, C. et al. Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat. Rev. Cardiol. 15, 731–743 (2018).
Nasim et al. High-intensity interval training increase GATA4, CITED4 and c-Kit and decreases C/EBPβ in rats after myocardial infarction. Life Sci. 221, 319–326 (2019).
Eskandari, A., Soori, R., Choobineh, S. & Tirani, Z. M. Exercise promotes heart regeneration in aged rats by increasing regenerative factors in myocardial tissue. Physiol. Int. 107, 166–176 (2020).
Gulsin, G. S. et al. Cardiovascular determinants of aerobic exercise capacity in adults with type 2 diabetes. Diabetes Care 43, 2248–2256 (2020).
Zhang, H. et al. Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming. Nat. Metab. 3, 843–858 (2021).
De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).
Wilson, R. J. et al. Voluntary running protects against neuromuscular dysfunction following hindlimb ischemia-reperfusion in mice. J. Appl. Physiol. 126, 193–201 (2019).
Li, C. et al. Early wheel-running promotes functional recovery by improving mitochondria metabolism in olfactory ensheathing cells after ischemic stroke in rats. Behav. Brain Res. 361, 32–38 (2019).
Kehm, R. D. et al. Recreational physical activity is associated with reduced breast cancer risk in adult women at high risk for breast cancer: a cohort study of women selected for familial and genetic risk. Cancer Res. 80, 116–125 (2020).
Padr O, A. I. et al. Exercise training protects against cancer-induced cardiac remodeling in an animal model of urothelial carcinoma. Arch. Biochem. Biophys. 645, 12–18 (2018).
Hagar, A. et al. Endurance training slows breast tumor growth in mice by suppressing Treg cells recruitment to tumors. BMC Cancer 19, 536 (2019).
Vervoort, M. Regeneration and development in animals. Biol. Theory 6, 25–35 (2011).
Poss, K. D. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat. Rev. Genet. 11, 710–722 (2010).
Galliot, B., Crescenzi, M., Jacinto, A. & Tajbakhsh, S. Trends in tissue repair and regeneration. Development 144, 357–364 (2017).
Fu, X. Repair cell first, then regenerate the tissues and organs. Mil. Med. Res. 8, 2 (2021).
Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).
He, L. & Zhou, B. Cardiomyocyte proliferation: remove brakes and push accelerators. Cell Res. 27, 959–960 (2017).
Nakada, D., Levi, B. P. & Morrison, S. J. Integrating physiological regulation with stem cell and tissue homeostasis. Neuron 70, 703–718 (2011).
Armada-da-Silva, P. A., Pereira, C., Amado, S. & Veloso, A. P. Role of physical exercise for improving posttraumatic nerve regeneration. Int. Rev. Neurobiol. 109, 125–149 (2013).
Zarei-Kheirabadi, M. et al. Human embryonic stem cell-derived neural stem cells encapsulated in hyaluronic acid promotes regeneration in a contusion spinal cord injured rat. Int. J. Biol. Macromol. 148, 1118–1129 (2020).
Kim, S. G. A cell-based approach to dental pulp regeneration using mesenchymal stem cells: a scoping review. Int. J. Mol. Sci. 22, 4357 (2021).
Čamernik, K. et al. Mesenchymal stem cells in the musculoskeletal system: from animal models to human tissue regeneration? Stem Cell Rev. Rep. 14, 346–369 (2018).
Spitzhorn, L. et al. Transplanted human pluripotent stem cell-derived mesenchymal stem cells support liver regeneration in Gunn rats. Stem Cells Dev. 27, 1702–1714 (2018).
Granata, C. et al. High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content. Nat. Commun. 12, 7056 (2021).
Janssen, I., Heymsfield, S. B., Wang, Z. & Ross, R. Skeletal muscle mass and distribution in 468 men and women aged 18–88 yr. J. Appl. Physiol. 89, 81–88 (2000).
Jarvinen, T. A. et al. Muscle injuries: optimising recovery. Best. Pract. Res. Clin. Rheumatol. 21, 317–331 (2007).
Joyner, M. J. & Coyle, E. F. Endurance exercise performance: the physiology of champions. J. Physiol. 586, 35–44 (2008).
Qaisar, R., Bhaskaran, S. & Van Remmen, H. Muscle fiber type diversification during exercise and regeneration. Free Radic. Biol. Med. 98, 56–67 (2016).
Konopka, A. R. & Harber, M. P. Skeletal muscle hypertrophy after aerobic exercise training. Exerc. Sport Sci. Rev. 42, 53–61 (2014).
Koulmann, N. et al. Physical exercise during muscle regeneration improves recovery of the slow/oxidative phenotype. Muscle Nerve 55, 91–100 (2016).
Richard-Bulteau, H., Serrurier, B., Crassous, B., Banzet, S. & Koulmann, N. Recovery of skeletal muscle mass after extensive injury: positive effects of increased contractile activity. Am. J. Physiol. Cell Physiol. 294, C467–C476 (2008).
Hughes, D. C., Ellefsen, S. & Baar, K. Adaptations to endurance and strength training. Cold Spring Harb. Perspect. Med. 8, a29769 (2018).
Friedmann-Bette et al. Strength training effects on muscular regeneration after ACL reconstruction. Med. Sci. Sports Exerc. 50, 1152–1161 (2018).
Izadi, M. R., Habibi, A., Khodabandeh, Z. & Nikbakht, M. Synergistic effect of high-intensity interval training and stem cell transplantation with amniotic membrane scaffold on repair and rehabilitation after volumetric muscle loss injury. Cell Tissue Res. 383, 765–779 (2021).
Grounds, M. D. The need to more precisely define aspects of skeletal muscle regeneration. Int. J. Biochem. Cell Biol. 56, 56–65 (2014).
Kaczmarek, A. et al. The role of satellite cells in skeletal muscle regeneration—the effect of exercise and age. Biology 10, 1056 (2021).
Yin, H., Price, F. & Rudnicki, M. A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013).
Fukada, S. & Nakamura, A. Exercise/resistance training and muscle stem cells. Endocrinol. Metab. 36, 737–744 (2021).
Murach, K. A., Fry, C. S., Dupont Versteegden, E. E., McCarthy, J. J. & Peterson, C. A. Fusion and beyond: satellite cell contributions to loading‐induced skeletal muscle adaptation. FASEB J. 35, e21893 (2021).
Perandini, L. A., Chimin, P., Lutkemeyer, D. D. S. & Câmara, N. O. S. Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche? FASEB J. 285, 1973–1984 (2018).
Wang, H. et al. Altered macrophage phenotype transition impairs skeletal muscle regeneration. Am. J. Pathol. 184, 1167–1184 (2014).
Walton, R. G. et al. Human skeletal muscle macrophages increase following cycle training and are associated with adaptations that may facilitate growth. Sci. Rep. 9, 969 (2019).
Minari, A. L. A., Oyama, L. M. & Dos Santos, R. V. T. Downhill exercise-induced changes in gene expression related with macrophage polarization and myogenic cells in the triceps long head of rats. Inflammation 38, 209–217 (2015).
Madaro, L. et al. Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat. Cell Biol. 20, 917–927 (2018).
Farup, J., Madaro, L., Puri, P. L. & Mikkelsen, U. R. Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease. Cell Death Dis. 6, e1830 (2015).
Joe, A. W. B. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).
Saito, Y., Chikenji, T. S., Matsumura, T., Nakano, M. & Fujimiya, M. Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors. Nat. Commun. 11, 889 (2020).
Specker, B. & Minett, M. Can physical activity improve peak bone mass? Curr. Osteoporos. Rep. 11, 229–236 (2013).
Kemmler, W., Bebenek, M., von Stengel, S. & Bauer, J. Peak-bone-mass development in young adults: effects of study program related levels of occupational and leisure time physical activity and exercise. A prospective 5-year study. Osteoporos. Int. 26, 653–662 (2015).
Gomez-Cabello, A., Ara, I., Gonzalez-Aguero, A., Casajus, J. A. & Vicente-Rodriguez, G. Effects of training on bone mass in older adults: a systematic review. Sports Med. 42, 301–325 (2012).
Suominen, H. Muscle training for bone strength. Aging Clin. Exp. Res. 18, 85–93 (2006).
Shahabi, S. et al. The effects of 8-week resistance and endurance trainings on bone strength compared to irisin injection protocol in mice. Adv. Biomed. Res. 10, 40 (2021).
Turner, C. H. Three rules for bone adaptation to mechanical stimuli. Bone 23, 399–407 (1998).
Davison, S. et al. Exercise-based correlates to calcaneal osteogenesis produced by a chronic training intervention. Bone 128, 115049 (2019).
Maes, C. Role and regulation of vascularization processes in endochondral bones. Calcif. Tissue Int. 92, 307–323 (2013).
Yao, Z. et al. Increase of both angiogenesis and bone mass in response to exercise depends on VEGF. J. Bone Miner. Res. 19, 1471–1480 (2004).
Holstein, J. H. et al. Exercise enhances angiogenesis during bone defect healing in mice. J. Orthop. Res. 29, 1086–1092 (2011).
Wazzani, R. et al. Physical activity and bone vascularization: a way to explore in bone repair context? Life 11, 783 (2021).
Flanigan, D. C., Harris, J. D., Trinh, T. Q., Siston, R. A. & Brophy, R. H. Prevalence of chondral defects in athletes’ knees: a systematic review. Med. Sci. Sports Exerc. 42, 1795–1801 (2010).
Perera, J. R., Gikas, P. D. & Bentley, G. The present state of treatments for articular cartilage defects in the knee. Ann. R. Coll. Surg. Engl. 94, 381–387 (2012).
Wellsandt, E. & Golightly, Y. Exercise in the management of knee and hip osteoarthritis. Curr. Opin. Rheumatol. 30, 151–159 (2018).
Raposo, F., Ramos, M. & Lúcia Cruz, A. Effects of exercise on knee osteoarthritis: a systematic review. Musculoskelet. Care 19, 399–435 (2021).
Vincent, K. R., Vasilopoulos, T., Montero, C. & Vincent, H. K. Eccentric and concentric resistance exercise comparison for knee osteoarthritis. Med. Sci. Sports Exerc. 51, 1977–1986 (2019).
Iijima, H. et al. Exercise intervention increases expression of bone morphogenetic proteins and prevents the progression of cartilage-subchondral bone lesions in a post-traumatic rat knee model. Osteoarthr. Cartil. 24, 1092–1102 (2016).
Assis, L. et al. Aerobic exercise training and low-level laser therapy modulate inflammatory response and degenerative process in an experimental model of knee osteoarthritis in rats. Osteoarthr. Cartil. 24, 169–177 (2016).
Steele, J., Bruce-Low, S., Smith, D., Osborne, N. & Thorkeldsen, A. Can specific loading through exercise impart healing or regeneration of the intervertebral disc? Spine J. 15, 2117–2121 (2015).
Fernandes, T. L. et al. Macrophage: a potential target on cartilage regeneration. Front. Immunol. 11, 111 (2020).
Kubosch, E. J. et al. The potential for synovium-derived stem cells in cartilage repair. Curr. Stem Cell Res. Ther. 13, 174–184 (2018).
Benmassaoud, M. M., Gultian, K. A., DiCerbo, M. & Vega, S. L. Hydrogel screening approaches for bone and cartilage tissue regeneration. Ann. NY Acad. Sci. 1460, 25–42 (2019).
Smith, J. K. Exercise as an adjuvant to cartilage regeneration therapy. Int. J. Mol. Sci. 21, 9471 (2020).
Liu, Y. et al. Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits. Sci. Transl. Med. 14, eabi7282 (2022).
Yokota, H., Leong, D. J. & Sun, H. B. Mechanical loading: bone remodeling and cartilage maintenance. Curr. Osteoporos. Rep. 9, 237–242 (2011).
Tong, X. et al. The effect of exercise on the prevention of osteoporosis and bone angiogenesis. Biomed. Res. Int. 2019, 8171897 (2019).
Qi, M. C., Zou, S. J., Han, L. C., Zhou, H. X. & Hu, J. Expression of bone‐related genes in bone marrow MSCs after cyclic mechanical strain: implications for distraction osteogenesis. Int. J. Oral Sci. 1, 143–150 (2009).
Schmid, M., Kröpfl, J. M. & Spengler, C. M. Changes in circulating stem and progenitor cell numbers following acute exercise in healthy human subjects: a systematic review and meta-analysis. Stem Cell Rev. Rep. 17, 1091–1120 (2021).
Chan, C. K. F. et al. Identification of the human skeletal stem cell. Cell 175, 43–56 (2018).
Ortinau, L. C. et al. Identification of functionally distinct Mx1+αSMA+ periosteal skeletal stem cells. Cell Stem Cell 25, 784–796 (2019).
Kylmaoja, E., Nakamura, M. & Tuukkanen, J. Osteoclasts and remodeling based bone formation. Curr. Stem Cell Res. Ther. 11, 626–633 (2016).
Marędziak, M., Śmieszek, A., Chrząstek, K., Basinska, K. & Marycz, K. Physical activity increases the total number of bone-marrow-derived mesenchymal stem cells, enhances their osteogenic potential, and inhibits their adipogenic properties. Stem Cells Int. 2015, 379093 (2015).
Kreja, L., Liedert, A., Hasni, S., Claes, L. & Ignatius, A. Mechanical regulation of osteoclastic genes in human osteoblasts. Biochem. Biophys. Res. Commun. 368, 582–587 (2008).
Kish, K., Mezil, Y., Ward, W. E., Klentrou, P. & Falk, B. Effects of plyometric exercise session on markers of bone turnover in boys and young men. Eur. J. Appl. Physiol. 115, 2115–2124 (2015).
Udagawa, N. et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J. Bone Miner. Metab. 39, 19–26 (2021).
Sanchis-Gomar, F., Fiuza-Luces, C. & Lucia, A. Exercise as the master polypill of the 21st century for the prevention of cardiovascular disease. Int. J. Cardiol. 181, 360–361 (2015).
Lavie, C. J. et al. Exercise and the cardiovascular system. Circ. Res. 117, 207–219 (2015).
Utomi, V. et al. Systematic review and meta-analysis of training mode, imaging modality and body size influences on the morphology and function of the male athlete’s heart. Heart 99, 1727–1733 (2013).
Boström, P. et al. C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143, 1072–1083 (2010).
Vujic, A. et al. Exercise induces new cardiomyocyte generation in the adult mammalian heart. Nat. Commun. 9, 1659 (2018).
Bei, Y. et al. Cardiac cell proliferation is not necessary for exercise-induced cardiac growth but required for its protection against ischaemia/reperfusion injury. J. Cell. Mol. Med. 21, 1648–1655 (2017).
Bansal, A. et al. Proteomic analysis reveals late exercise effects on cardiac remodeling following myocardial infarction. J. Proteomics 73, 2041–2049 (2010).
Yengo, C. M., Zimmerman, S. D., McCormick, R. J. & Thomas, D. P. Exercise training post-MI favorably modifies heart extracellular matrix in the rat. Med. Sci. Sports Exerc. 44, 1005–1012 (2012).
Haykowsky, M. et al. A meta-analysis of the effects of exercise training on left ventricular remodeling following myocardial infarction: start early and go longer for greatest exercise benefits on remodeling. Trials 12, 92 (2011).
Rahimi, M. et al. The effect of high intensity interval training on cardioprotection against ischemia-reperfusion injury in wistar rats. EXCLI J. 14, 237–246 (2015).
Jia, D., Hou, L., Lv, Y., Xi, L. & Tian, Z. Postinfarction exercise training alleviates cardiac dysfunction and adverse remodeling via mitochondrial biogenesis and SIRT1/PGC‐1α/PI3K/Akt signaling. J. Cell. Physiol. 234, 23705–23718 (2019).
Liu, X. et al. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab. 21, 584–595 (2015).
Otaka, N. et al. Myonectin is an exercise-induced myokine that protects the heart from ischemia-reperfusion injury. Circ. Res. 123, 1326–1338 (2018).
Shi, J. et al. miR-17-3p contributes to exercise-induced cardiac growth and protects against myocardial ischemia-reperfusion injury. Theranostics 7, 664–676 (2017).
Bei, Y. et al. Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury. Basic Res. Cardiol. 112, 38 (2017).
Garza, M. A. Cardiac remodeling and physical training post myocardial infarction. World J. Cardiol. 7, 52–64 (2015).
Garza, M. A., Wason, E. A., Cruger, J. R., Chung, E. & Zhang, J. Q. Strength training attenuates post-infarct cardiac dysfunction and remodeling. J. Physiol. Sci. 69, 523–530 (2019).
Mueller, S. et al. Effect of high-intensity interval training, moderate continuous training, or guideline-based physical activity advice on peak oxygen consumption in patients with heart failure with preserved ejection fraction. JAMA 325, 542–551 (2021).
Ellingsen, Ø. et al. High-intensity interval training in patients with heart failure with reduced ejection fraction. Circulation 135, 839–849 (2017).
Tan, J. et al. Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch. Cell Rep. 38, 110468 (2022).
Sharman, J. E., La Gerche, A. & Coombes, J. S. Exercise and cardiovascular risk in patients with hypertension. Am. J. Hypertens. 28, 147–158 (2015).
Antunes, J. M. M., Ferreira, R. M. P. & Moreira-Gonçalves, D. Exercise training as therapy for cancer-induced cardiac cachexia. Trends Mol. Med. 24, 709–727 (2018).
Bond, A. M. et al. Differential timing and coordination of neurogenesis and astrogenesis in developing mouse hippocampal subregions. Brain Sci. 10, 909 (2020).
Moreno-Jiménez, E. P. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 25, 554–560 (2019).
Boldrini, M. et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22, 589–599 (2018).
van Praag, H. Neurogenesis and exercise: past and future directions. Neuromol. Med. 10, 128–140 (2008).
Nam, S. M. et al. Effects of treadmill exercise on neural stem cells, cell proliferation, and neuroblast differentiation in the subgranular zone of the dentate gyrus in cyclooxygenase-2 knockout mice. Neurochem. Res. 38, 2559–2569 (2013).
Firth, J. et al. Effect of aerobic exercise on hippocampal volume in humans: a systematic review and meta-analysis. Neuroimage 166, 230–238 (2018).
Batcho, C., Stoquart, G. & Thonnard, J. Brisk walking can promote functional recovery in chronic stroke patients. J. Rehabil. Med. 45, 854–859 (2013).
Cumming, T. B., Tyedin, K., Churilov, L., Morris, M. E. & Bernhardt, J. The effect of physical activity on cognitive function after stroke: a systematic review. Int. Psychogeriatr. 24, 557–567 (2012).
Marzolini, S., Oh, P., McIlroy, W. & Brooks, D. The effects of an aerobic and resistance exercise training program on cognition following stroke. Neurorehab. Neural Repair. 27, 392–402 (2013).
Pang, M. Y. C., Charlesworth, S. A., Lau, R. W. K. & Chung, R. C. K. Using aerobic exercise to improve health outcomes and quality of life in stroke: evidence-based exercise prescription recommendations. Cerebrovasc. Dis. 35, 7–22 (2013).
Vahlberg, B., Cederholm, T., Lindmark, B., Zetterberg, L. & Hellström, K. Short-term and long-term effects of a progressive resistance and balance exercise program in individuals with chronic stroke: a randomized controlled trial. Disabil. Rehabil. 39, 1615–1622 (2016).
Mehta, S. et al. Resistance training for gait speed and total distance walked during the chronic stage of stroke: a meta-analysis. Top. Stroke Rehabil. 19, 471–478 (2014).
Hu, J. et al. Constraint-induced movement therapy enhances AMPA receptor-dependent synaptic plasticity in the ipsilateral hemisphere following ischemic stroke. Neural Regen. Res. 16, 319 (2021).
Shabanzadeh, A. P. et al. Modifying PTEN recruitment promotes neuron survival, regeneration, and functional recovery after CNS injury. Cell Death Dis. 10, 567 (2019).
Tang, Y. et al. Effects of treadmill exercise on cerebral angiogenesis and MT1-MMP expression after cerebral ischemia in rats. Brain Behav. 8, e1079 (2018).
Chang, A. et al. Neurogenesis in the chronic lesions of multiple sclerosis. Brain 131, 2366–2375 (2008).
Guo, L. Y., Lozinski, B. & Yong, V. W. Exercise in multiple sclerosis and its models: focus on the central nervous system outcomes. J. Neurosci. Res. 98, 509–523 (2020).
Sandrow-Feinberg, H. R. & Houlé, J. D. Exercise after spinal cord injury as an agent for neuroprotection, regeneration and rehabilitation. Brain Res. 1619, 12–21 (2015).
Chew, C. & Sengelaub, D. Exercise promotes recovery after motoneuron injury via hormonal mechanisms. Neural Regen. Res. 15, 1373 (2020).
Davaa, G. et al. Exercise ameliorates spinal cord injury by changing DNA methylation. Cells 10, 143 (2021).
Jung, S., Seo, T. & Kim, D. Treadmill exercise facilitates recovery of locomotor function through axonal regeneration following spinal cord injury in rats. J. Exerc. Rehabil. 12, 284–292 (2016).
Chang, W. et al. Locomotion dependent neuron-glia interactions control neurogenesis and regeneration in the adult zebrafish spinal cord. Nat. Commun. 12, 4857 (2021).
Hesp, Z. C. et al. Proliferating NG2-cell-dependent angiogenesis and scar formation alter axon growth and functional recovery after spinal cord injury in mice. J. Neurosci. 38, 1366–1382 (2018).
Stenudd, M., Sabelström, H. & Frisén, J. Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol. 72, 235–237 (2015).
Hackett, A. R. et al. Injury type-dependent differentiation of NG2 glia into heterogeneous astrocytes. Exp. Neurol. 308, 72–79 (2018).
Tashiro, S. et al. Current progress of rehabilitative strategies in stem cell therapy for spinal cord injury: a review. NPJ Regen. Med. 6, 81 (2021).
Takeoka, A. et al. Axon regeneration can facilitate or suppress hindlimb function after olfactory ensheathing glia transplantation. J. Neurosci. 31, 4298–4310 (2011).
Hwang, D. H. et al. Survival of neural stem cell grafts in the lesioned spinal cord is enhanced by a combination of treadmill locomotor training via insulin-like growth factor-1 signaling. J. Neurosci. 34, 12788–12800 (2014).
Benowitz, L. I. & Popovich, P. G. Inflammation and axon regeneration. Curr. Opin. Neurol. 24, 577–583 (2011).
Conforti, L., Gilley, J. & Coleman, M. P. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat. Rev. Neurosci. 15, 394–409 (2014).
Kluding, P. M. et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J. Diabetes Complicat. 26, 424–429 (2012).
Allet, L. et al. The gait and balance of patients with diabetes can be improved: a randomised controlled trial. Diabetologia 53, 458–466 (2010).
Zimmer, P. et al. Eight-week, multimodal exercise counteracts a progress of chemotherapy-induced peripheral neuropathy and improves balance and strength in metastasized colorectal cancer patients: a randomized controlled trial. Support. Care Cancer 26, 615–624 (2018).
Dhawan, S., Andrews, R., Kumar, L., Wadhwa, S. & Shukla, G. A randomized controlled trial to assess the effectiveness of muscle strengthening and balancing exercises on chemotherapy-induced peripheral neuropathic pain and quality of life among cancer patients. Cancer Nurs. 43, 269–280 (2020).
Ballestero-Pérez, R. et al. Effectiveness of nerve gliding exercises on carpal tunnel syndrome: a systematic review. J. Manip. Physiol. Ther. 40, 50–59 (2017).
Streckmann, F. et al. Exercise program improves therapy-related side-effects and quality of life in lymphoma patients undergoing therapy. Ann. Oncol. 25, 493–499 (2014).
Kleckner, I. R. et al. Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial. Support. Care Cancer 26, 1019–1028 (2018).
Bland, K. A. et al. Effect of exercise on taxane chemotherapy–induced peripheral neuropathy in women with breast cancer: a randomized controlled trial. Clin. Breast Cancer 19, 411–422 (2019).
Neto, W. K. et al. Ladder-based resistance training elicited similar ultrastructural adjustments in forelimb and hindlimb peripheral nerves of young adult Wistar rats. Exp. Brain Res. 239, 2583–2592 (2021).
Martins, D. F. et al. Long-term regular eccentric exercise decreases neuropathic pain-like behavior and improves motor functional recovery in an axonotmesis mouse model: the role of insulin-like growth factor-1. Mol. Neurobiol. 55, 6155–6168 (2018).
de Moraes, A. A., de Almeida, C. A. S., Lucas, G., Thomazini, J. A. & DeMaman, A. S. Effect of swimming training on nerve morphological recovery after compressive injury. Neurol. Res. 40, 955–962 (2018).
Liao, C. et al. Effects of swimming exercise on nerve regeneration in a rat sciatic nerve transection model. Biomedicine 7, 3 (2017).
Coelho Ferreira, M. et al. Effects of two intensities of treadmill exercise on neuromuscular recovery after median nerve crush injury in Wistar rats. J. Exerc. Rehabil. 15, 392–400 (2019).
Michalopoulos, G. K. & Bhushan, B. Liver regeneration: biological and pathological mechanisms and implications. Nat. Rev. Gastroenterol. Hepatol. 18, 40–55 (2021).
Linecker, M. et al. Exercise improves outcomes of surgery on fatty liver in mice. Ann. Surg. 271, 347–355 (2020).
Fard Aghaie, M. H. et al. The effects of physical prehabilitation: Improved liver regeneration and mitochondrial function after ALPPS operation in a rodent model. J. Hepatobiliary Pancreat. Sci. 28, 692–702 (2021).
Emery, C. F., Kiecolt-Glaser, J. K., Glaser, R., Malarkey, W. B. & Frid, D. J. Exercise accelerates wound healing among healthy older adults: a preliminary investigation. J. Gerontol. A Biol. Sci. Med. Sci. 60, 1432–1436 (2005).
Keylock, K. T. et al. Exercise accelerates cutaneous wound healing and decreases wound inflammation in aged mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R179–R184 (2008).
Mutlak, O., Aslam, M. & Standfield, N. The influence of exercise on ulcer healing in patients with chronic venous insufficiency. Int. Angiol. 37, 160–168 (2018).
Zogaib, F. G. & Monte-Alto-Costa, A. Moderate intensity physical training accelerates healing of full-thickness wounds in mice. Braz. J. Med. Biol. Res. 44, 1025–1035 (2011).
Keylock, T., Meserve, L. & Wolfe, A. Low-intensity exercise accelerates wound healing in diabetic mice. Wounds 30, 68–71 (2018).
Emmons, R., Niemiro, G. M., Owolabi, O. & De Lisio, M. Acute exercise mobilizes hematopoietic stem and progenitor cells and alters the mesenchymal stromal cell secretome. J. Appl. Physiol. 120, 624–632 (2016).
Emmons, R., Ngu, M., Xu, G., Hernández-Saavedra, D. & Lisio, M. D. Effects of obesity and exercise on bone marrow progenitor cells following radiation. Med. Sci. Sports Exerc. 51, 1126–1136 (2019).
Frodermann, V. et al. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells. Nat. Med. 25, 1761–1771 (2019).
Stelzer, I. et al. Ultra-endurance exercise induces stress and inflammation and affects circulating hematopoietic progenitor cell function. Scand. J. Med. Sci. Sports 25, e442–e450 (2015).
Appelbaum, F. R. Hematopoietic-cell transplantation at 50. N. Engl. J. Med. 357, 1472–1475 (2007).
De Lisio, M., Baker, J. M. & Parise, G. Exercise promotes bone marrow cell survival and recipient reconstitution post-bone marrow transplantation, which is associated with increased survival. Exp. Hematol. 41, 143–154 (2013).
Wiskemann, J. & Huber, G. Physical exercise as adjuvant therapy for patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 41, 321–329 (2008).
Baumann, F. T. et al. Physical activity for patients undergoing an allogeneic hematopoietic stem cell transplantation: benefits of a moderate exercise intervention. Eur. J. Haematol. 87, 148–156 (2011).
Khan, K. M. & Scott, A. Mechanotherapy: how physical therapists’ prescription of exercise promotes tissue repair. Br. J. Sports Med. 43, 247–252 (2009).
Magliulo, L., Bondi, D., Pini, N., Marramiero, L. & Di Filippo, E. S. The wonder exerkines—novel insights: a critical state-of-the-art review. Mol. Cell. Biochem. 477, 105–113 (2022).
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).
Hoffmann, C. & Weigert, C. Skeletal muscle as an endocrine organ: the role of myokines in exercise adaptations. Csh. Perspect. Med. 7, a29793 (2017).
Han, Y., You, X., Xing, W., Zhang, Z. & Zou, W. Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 6, 16 (2018).
Henriksen, T., Green, C. & Pedersen, B. K. Myokines in myogenesis and health. Recent Pat. Biotechnol. 6, 167–171 (2012).
Herrmann, M. et al. Interactions between muscle and bone—where physics meets biology. Biomolecules 10, 432 (2020).
Monemian, E. A. et al. Tissue regeneration from mechanical stretching of cell-cell adhesion. Tissue Eng. C Methods 25, 631–640 (2019).
Castillo, A. B. & Leucht, P. Bone homeostasis and repair: forced into shape. Curr. Rheumatol. Rep. 17, 58 (2015).
Dolan, C. P. et al. Digit specific denervation does not inhibit mouse digit tip regeneration. Dev. Biol. 486, 71–80 (2022).
Murthy, S. E., Dubin, A. E. & Patapoutian, A. Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat. Rev. Mol. Cell Biol. 18, 771–783 (2017).
Gudipaty, S. A. et al. Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543, 118–121 (2017).
Kefauver, J. M., Ward, A. B. & Patapoutian, A. Discoveries in structure and physiology of mechanically activated ion channels. Nature 587, 567–576 (2020).
He, L., Si, G., Huang, J., Samuel, A. D. T. & Perrimon, N. Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature 555, 103–106 (2018).
Sun, W. et al. The mechanosensitive Piezo1 channel is required for bone formation. ELife 8, e47454 (2019).
Li, X. et al. Stimulation of Piezo1 by mechanical signals promotes bone anabolism. ELife 8, e49631 (2019).
Beech, D. J. Endothelial Piezo1 channels as sensors of exercise. J. Physiol. 596, 979–984 (2018).
Rozo, M., Li, L. & Fan, C. Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice. Nat. Med. 22, 889–896 (2016).
Boppart, M. D. & Mahmassani, Z. S. Integrin signaling: linking mechanical stimulation to skeletal muscle hypertrophy. Am. J. Physiol. Cell Physiol. 317, C629–C641 (2019).
Geiger, B., Spatz, J. P. & Bershadsky, A. D. Environmental sensing through focal adhesions. Nat. Rev. Mol. Cell Biol. 10, 21–33 (2009).
Plotkin, L. I., Davis, H. M., Cisterna, B. A. & Sáez, J. C. Connexins and pannexins in bone and skeletal muscle. Curr. Osteoporos. Rep. 15, 326–334 (2017).
Shen, H., Grimston, S., Civitelli, R. & Thomopoulos, S. Deletion of Connexin43 in osteoblasts/osteocytes leads to impaired muscle formation in mice. J. Bone Miner. Res. 30, 596–605 (2015).
Ren, Q., Chen, J. & Liu, Y. LRP5 and LRP6 in Wnt signaling: similarity and divergence. Front. Cell Dev. Biol. 9, 670960 (2021).
Williams, B. O. LRP5: from bedside to bench to bone. Bone 102, 26–30 (2017).
Zhao, L., Shim, J. W., Dodge, T. R., Robling, A. G. & Yokota, H. Inactivation of Lrp5 in osteocytes reduces Young’s modulus and responsiveness to the mechanical loading. Bone 54, 35–43 (2013).
Mehta, V. et al. The guidance receptor plexin D1 is a mechanosensor in endothelial cells. Nature 578, 290–295 (2020).
Li, X., Kordsmeier, J. & Xiong, J. New advances in osteocyte mechanotransduction. Curr. Osteoporos. Rep. 19, 101–106 (2021).
Wackerhage, H., Schoenfeld, B. J., Hamilton, D. L., Lehti, M. & Hulmi, J. J. Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise. J. Appl. Physiol. 126, 30–43 (2019).
Song, Y. et al. The mechanosensitive ion channel Piezo inhibits axon regeneration. Neuron 102, 373–389 (2019).
Li, F. et al. The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation. Nat. Commun. 12, 3845 (2021).
Song, Z. et al. Mechanosensing in liver regeneration. Semin. Cell Dev. Biol. 71, 153–167 (2017).
Lorenz, L. et al. Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival. Nature 562, 128–132 (2018).
Lyon, R. C., Zanella, F., Omens, J. H. & Sheikh, F. Mechanotransduction in cardiac hypertrophy and failure. Circ. Res. 116, 1462–1476 (2015).
Jiang, F. et al. The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction. Nat. Commun. 12, 869 (2021).
Tsata, V. & Beis, D. In full force. Mechanotransduction and morphogenesis during homeostasis and tissue regeneration. J. Cardiovasc. Dev. Dis. 7, 40 (2020).
Santos, L., Ugun-Klusek, A., Coveney, C. & Boocock, D. J. Multiomic analysis of stretched osteocytes reveals processes and signalling linked to bone regeneration and cancer. NPJ Regen. Med. 6, 32 (2021).
Tanaka, S. & Matsumoto, T. Sclerostin: from bench to bedside. J. Bone Miner. Metab. 39, 332–340 (2021).
Crossland, H. et al. Focal adhesion kinase is required for IGF-1-mediated growth of skeletal muscle cells via a TSC2/mTOR/S6K1-associated pathway. Am. J. Physiol. Endocrinol. Metab. 305, E183–E193 (2013).
Sato, T. et al. A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction. Nat. Commun. 11, 3282 (2020).
Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).
Wang, L. et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579–582 (2016).
Zheng, Y. & Pan, D. The Hippo signaling pathway in development and disease. Dev. Cell 50, 264–282 (2019).
Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: Hippo signaling and beyond. Physiol. Rev. 94, 1287–1312 (2014).
Ma, S., Meng, Z., Chen, R. & Guan, K. The Hippo pathway: biology and pathophysiology. Annu. Rev. Biochem. 88, 577–604 (2019).
Chang, Y., Wu, J., Wang, C. & Jang, A. C. C. Hippo signaling-mediated mechanotransduction in cell movement and cancer metastasis. Front. Mol. Biosci. 6, 157 (2020).
Liu, Q. et al. Suppressing Hippo signaling in the stem cell niche promotes skeletal muscle regeneration. Stem Cells 39, 737–749 (2021).
Gabriel, B. M., Hamilton, D. L., Tremblay, A. M. & Wackerhage, H. The Hippo signal transduction network for exercise physiologists. J. Appl. Physiol. 120, 1105–1117 (2016).
Ziouti, F. et al. NOTCH signaling is activated through mechanical strain in human bone marrow-derived mesenchymal stromal cells. Stem Cells Int. 2019, 5150634 (2019).
Stassen, O. M. J. A., Ristori, T. & Sahlgren, C. M. Notch in mechanotransduction–from molecular mechanosensitivity to tissue mechanostasis. J. Cell Sci. 133, jcs250738 (2020).
Arthur, S. T. & Cooley, I. D. The effect of physiological stimuli on sarcopenia; impact of Notch and Wnt signaling on impaired aged skeletal muscle repair. Int. J. Biol. Sci. 8, 731–760 (2012).
Bi, P. et al. Stage-specific effects of Notch activation during skeletal myogenesis. ELife 5, e17355 (2016).
Fujimaki, S. et al. Functional overload enhances satellite cell properties in skeletal muscle. Stem Cells Int. 2016, 7619418 (2016).
Lin, J. et al. Swimming exercise stimulates IGF1/PI3K/Akt and AMPK/SIRT1/PGC1α survival signaling to suppress apoptosis and inflammation in aging hippocampus. Aging 12, 6852–6864 (2020).
Feng, L., Li, B., Xi, Y., Cai, M. & Tian, Z. Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction. Am. J. Physiol. Cell Physiol. 322, C164–C176 (2022).
Kraemer, W. J., Ratamess, N. A. & Nindl, B. C. Recovery responses of testosterone, growth hormone, and IGF-1 after resistance exercise. J. Appl. Physiol. 122, 549–558 (2017).
Yu, T., Chang, Y., Gao, X., Li, H. & Zhao, P. Dynamic expression and the role of BDNF in exercise-induced skeletal muscle regeneration. Int. J. Sports Med. 38, 959–966 (2017).
Li, S. et al. MOTS-c and exercise restore cardiac function by activating of NRG1-ErbB signaling in diabetic rats. Front. Endocrinol. 13, 812032 (2022).
Yoshida, T. & Delafontaine, P. Mechanisms of IGF-1-mediated regulation of skeletal muscle hypertrophy and atrophy. Cells 9, 1970 (2020).
Fink, J., Schoenfeld, B. J. & Nakazato, K. The role of hormones in muscle hypertrophy. Phys. Sportsmed. 46, 129–134 (2018).
Guntur, A. R. & Rosen, C. J. IGF-1 regulation of key signaling pathways in bone. Bonekey Rep. 2, 437 (2013).
Bikle, D. D. et al. Role of IGF-I signaling in muscle bone interactions. Bone 80, 79–88 (2015).
McMullen, J. R. et al. Phosphoinositide 3-kinase(p110α) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc. Natl Acad. Sci. USA 100, 12355–12360 (2003).
Kim, J. et al. Insulin-like growth factor i receptor signaling is required for exercise-induced cardiac hypertrophy. Mol. Endocrinol. 22, 2531–2543 (2008).
Gumà, A., Martínez-Redondo, V., López-Soldado, I., Cantó, C. & Zorzano, A. Emerging role of neuregulin as a modulator of muscle metabolism. Am. J. Physiol. Endocrinol. Metab. 298, E742–E750 (2010).
D Uva, G. et al. ERBB2 triggers mammalian heart regeneration bypromoting cardiomyocyte dedifferentiation andproliferation. Nat. Cell Biol. 17, 627–638 (2015).
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).
Gubert, C. & Hannan, A. J. Exercise mimetics: harnessing the therapeutic effects of physical activity. Nat. Rev. Drug Discov. 20, 862–879 (2021).
Li, Y. et al. Protection against acute cerebral ischemia/reperfusion injury by Leonuri Herba Total Alkali via modulation of BDNF-TrKB-PI3K/Akt signaling pathway in rats. Biomed. Pharmacother. 133, 111021 (2021).
Chang, M., Park, C., Rhie, S., Shim, W. & Kim, D. Early treadmill exercise increases macrophage migration inhibitory factor expression after cerebral ischemia/reperfusion. Neural Regen. Res. 14, 1230–1236 (2019).
Zhang, Q., Deng, X., Sun, X., Xu, J. & Sun, F. Exercise promotes axon regeneration of newborn striatonigral and corticonigral projection neurons in rats after ischemic stroke. PLoS ONE 8, e80139 (2013).
Kowiański, P. et al. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell. Mol. Neurobiol. 38, 579–593 (2018).
Liu, P. Z. & Nusslock, R. Exercise-mediated neurogenesis in the hippocampus via BDNF. Front. Neurosci. 12, 52 (2018).
Bilchak, J. N., Caron, G. & Cote, M. P. Exercise-induced plasticity in signaling pathways involved in motor recovery after spinal cord injury. Int. J. Mol. Sci. 22, 4858 (2021).
Weishaupt, N., Blesch, A. & Fouad, K. BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp. Neurol. 238, 254–264 (2012).
McGregor, C. E. & English, A. W. The role of BDNF in peripheral nerve regeneration: activity-dependent treatments and Val66Met. Front. Cell. Neurosci. 12, 522 (2019).
English, A. W., Wilhelm, J. C. & Ward, P. J. Exercise, neurotrophins, and axon regeneration in the PNS. Physiology 29, 437–445 (2014).
Reddy, L. V. K., Murugan, D., Mullick, M., Begum Moghal, E. T. & Sen, D. Recent approaches for angiogenesis in search of successful tissue engineering and regeneration. Curr. Stem Cell Res. Ther. 15, 111–134 (2020).
Hu, K. & Olsen, B. R. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone 91, 30–38 (2016).
Zhang, J. et al. Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization. Cell Metab. 31, 1136–1153 (2020).
Shibuya, M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J. Biochem. Mol. Biol. 39, 469–478 (2006).
Melincovici, C. S. et al. Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom. J. Morphol. Embryol. 59, 455–467 (2018).
Tang, K., Xia, F. C., Wagner, P. D. & Breen, E. C. Exercise-induced VEGF transcriptional activation in brain, lung and skeletal muscle. Respir. Physiol. Neurobi. 170, 16–22 (2010).
Pourheydar, B., Biabanghard, A., Azari, R., Khalaji, N. & Chodari, L. Exercise improves aging-related decreased angiogenesis through modulating VEGF-A, TSP-1 and p-NF-Ƙb protein levels in myocardiocytes. J. Cardiovasc. Thorac. Res. 12, 129–135 (2020).
Tryfonos, A. et al. Exercise training enhances angiogenesis-related gene responses in skeletal muscle of patients with chronic heart failure. Cells 10, 1915 (2021).
Chen, L., Bai, J. & Li, Y. miR-29 mediates exercise-induced skeletal muscle angiogenesis by targeting VEGFA, COL4A1 and COL4A2 via the PI3K/Akt signaling pathway. Mol. Med. Rep. 22, 661–670 (2020).
Da, Y. et al. Mechanical stress promotes biological functions of C2C12 myoblasts by activating PI3K/AKT/mTOR signaling pathway. Mol. Med. Rep. 21, 470–477 (2019).
Song, F. et al. Mechanical stress regulates osteogenesis and adipogenesis of rat mesenchymal stem cells through PI3K/Akt/GSK-3β/β-Catenin signaling pathway. Biomed. Res. Int. 2017, 6027402 (2017).
Liu, M. et al. Phosphorylated GSK-3β protects stress-induced apoptosis of myoblasts via the PI3K/Akt signaling pathway. Mol. Med. Rep. 22, 317–327 (2020).
Liang, J. et al. Promotion of aerobic exercise induced angiogenesis is associated with decline in blood pressure in hypertension. Hypertension 77, 1141–1153 (2021).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Watson, K. & Baar, K. mTOR and the health benefits of exercise. Semin. Cell Dev. Biol. 36, 130–139 (2014).
Baraldo, M. et al. Skeletal muscle mTORC1 regulates neuromuscular junction stability. J. Cachexia Sarcopenia Muscle 11, 208–225 (2020).
Chen, Z. et al. Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis. Theranostics 10, 6448–6466 (2020).
Liao, J., Li, Y., Zeng, F. & Wu, Y. Regulation of mTOR pathway in exercise-induced cardiac hypertrophy. Int. J. Sports Med. 36, 343–350 (2015).
Chen, K. et al. Exercise training improves motor skill learning via selective activation of mTOR. Sci. Adv. 5, w1888 (2019).
Kar, A. N. et al. MicroRNAs 21 and 199a-3p regulate axon growth potential through modulation of Pten and mTor mRNAs. eNeuro 8, 121–155 (2021).
Valvezan, A. J. & Manning, B. D. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333 (2019).
Deleyto-Seldas, N. & Efeyan, A. The mTOR-autophagy axis and the control of metabolism. Front. Cell Dev. Biol. 9, 655731 (2021).
Jang, Y. Endurance exercise-induced expression of autophagy-related protein coincides with anabolic expression and neurogenesis in the hippocampus of the mouse brain. Neuroreport 31, 442–449 (2020).
Ding, S. et al. C/EBPB-CITED4 in exercised heart. Adv. Exp. Med. Biol. 1000, 247–259 (2017).
Lerchenmüller, C. et al. CITED4 protects against adverse remodeling in response to physiological and pathological stress. Circ. Res. 127, 631–646 (2020).
Bezzerides, V. J. et al. CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury. JCI Insight 1, e85904 (2016).
Bahramian, A., Mirzaei, B., Karimzadeh, F., Ramhmaninia, F. & Hemmatinafar, M. The effects of exercise training intensity on the expression of C/EBPβ and CITED4 in rats with myocardial infarction. Asian J. Sports Med. 9, e59300 (2018).
Ryall, K. A., Bezzerides, V. J., Rosenzweig, A. & Saucerman, J. J. Phenotypic screen quantifying differential regulation of cardiac myocyte hypertrophy identifies CITED4 regulation of myocyte elongation. J. Mol. Cell. Cardiol. 72, 74–84 (2014).
Zeng, Z. et al. Exercise-induced autophagy suppresses sarcopenia through Akt/mTOR and Akt/FoxO3a signal pathways and AMPK-mediated mitochondrial quality control. Front. Physiol. 11, 583478 (2020).
Sanchez, A. M. J., Candau, R. B. & Bernardi, H. FoxO transcription factors: their roles in the maintenance of skeletal muscle homeostasis. Cell. Mol. Life Sci. 71, 1657–1671 (2014).
Rathbone, C. R., Booth, F. W. & Lees, S. J. FoxO3a preferentially induces p27Kip1 expression while impairing muscle precursor cell-cycle progression. Muscle Nerve 37, 84–89 (2008).
Liu, C. et al. Effect of RNA oligonucleotide targeting Foxo-1 on muscle growth in normal and cancer cachexia mice. Cancer Gene Ther. 14, 945–952 (2007).
Wen, X., Jiao, L. & Tan, H. MAPK/ERK pathway as a central regulator in vertebrate organ regeneration. Int. J. Mol. Sci. 23, 1464 (2022).
Aharonov, A. et al. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat. Cell Biol. 22, 1346–1356 (2020).
Tane, S. et al. CDK inhibitors, p21Cip1 and p27Kip1, participate in cell cycle exit of mammalian cardiomyocytes. Biochem. Biophys. Res. Commun. 443, 1105–1109 (2014).
Mohamed, T. et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 173, 104–116 (2018).
Zhu, L. et al. Remifentanil preconditioning promotes liver regeneration via upregulation of β-arrestin 2/ERK/cyclin D1 pathway. Biochem. Biophys. Res. Commun. 557, 69–76 (2021).
Liu, W. et al. Physical exercise promotes proliferation and differentiation of endogenous neural stem cells via ERK in rats with cerebral infarction. Mol. Med. Rep. 18, 1455–1464 (2018).
Brett, J. O. et al. Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1. Nat. Metab. 2, 307–317 (2020).
Kwon, J. H., Moon, K. M. & Min, K. W. Exercise-induced myokines can explain the importance of physical activity in the elderly: an overview. Healthcare 8, 378 (2020).
Zhang, L. et al. Medium-intensity treadmill exercise exerts beneficial effects on bone modeling through bone marrow mesenchymal stromal cells. Front. Cell Dev. Biol. 8, 600639 (2020).
Iijima, H. et al. Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model. Osteoarthr. Cartil. 25, 964–975 (2017).
Zou, M. et al. The Smad dependent TGF-β and BMP signaling pathway in bone remodeling and therapies. Front. Mol. Biosci. 8, 593310 (2021).
Zuo, C. et al. Osteoblastogenesis regulation signals in bone remodeling. Osteoporos. Int. 23, 1653–1663 (2012).
Wu, M., Chen, G. & Li, Y. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 4, 16009 (2016).
Chen, G., Deng, C. & Li, Y. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci. 8, 272–288 (2012).
Valladares-Ide, D. et al. Activation of protein synthesis, regeneration, and MAPK signaling pathways following repeated bouts of eccentric cycling. Am. J. Physiol. Endocrinol. Metab. 317, E1131–E1139 (2019).
Fan, W. & Evans, R. M. Exercise mimetics: impact on health and performance. Cell Metab. 25, 242–247 (2017).
Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).
Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).
Chen, H., Fan, W., He, H. & Huang, F. PGC-1: a key regulator in bone homeostasis. J. Bone Miner. Metab. 40, 1–8 (2022).
Norrbom, J. et al. PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J. Appl. Physiol. 96, 189–194 (2004).
Koves, T. R. et al. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J. Biol. Chem. 280, 33588–33598 (2005).
Dinulovic, I., Furrer, R., Beer, M. & Ferry, A. Muscle PGC-1α modulates satellite cell number and proliferation by remodeling the stem cell niche. Skelet. Muscle 6, 39 (2016).
Handschin, C. The biology of PGC-1alpha and its therapeutic potential. Trends Pharmacol. Sci. 30, 322–329 (2009).
Sánchez-de-Diego, C. et al. Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program. iScience 15, 79–94 (2019).
Colaianni, G. et al. Deletion of the transcription factor PGC-1alpha in mice negatively regulates bone mass. Calcif. Tissue Int. 103, 638–652 (2018).
Wang, J. et al. Hippocampal PGC-1α-mediated positive effects on parvalbumin interneurons are required for the antidepressant effects of running exercise. Transl. Psychiatry 11, 222 (2021).
Wang, S., Dougherty, E. J. & Danner, R. L. PPARγ signaling and emerging opportunities for improved therapeutics. Pharmacol. Res. 111, 76–85 (2016).
McMeekin, L. J. et al. Estrogen-related receptor alpha (ERRα) is required for PGC-1α-dependent gene expression in the mouse brain. Neuroscience 479, 70–90 (2021).
Wang, L. et al. mTORC1-PGC1 axis regulates mitochondrial remodeling during reprogramming. FEBS J. 287, 108–121 (2020).
Thirupathi, A. & de Souza, C. T. Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise. J. Physiol. Biochem. 73, 487–494 (2017).
Silva, F. C. D. et al. Effects of physical exercise on the expression of microRNAs: a systematic review. J. Strength Cond. Res. 34, 270–280 (2020).
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).
Allen, D. L. et al. Effects of spaceflight on murine skeletal muscle gene expression. J. Appl. Physiol. 106, 582–595 (2009).
Mytidou, C. et al. Age-related exosomal and endogenous expression patterns of miR-1, miR-133a, miR-133b, and miR-206 in skeletal muscles. Front. Physiol. 12, 708278 (2021).
Chen, J. et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet. 38, 228–233 (2006).
Elia, L. et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 120, 2377–2385 (2009).
Matheny, R. W. et al. RNA transcript expression of IGF-I/PI3K pathway components in regenerating skeletal muscle is sensitive to initial injury intensity. Growth Horm. IGF Res. 32, 14–21 (2017).
Lou, J. et al. Exercise promotes angiogenesis by enhancing endothelial cell fatty acid utilization via liver-derived extracellular vesicle miR-122-5p. J. Sport Health Sci. 11, 495–508 (2022).
Yang, H. et al. Treadmill exercise influences the microRNA profiles in the bone tissues of mice. Exp. Ther. Med. 22, 1035 (2021).
Zeng, H. et al. MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-β signalling in osteoblasts. Nat. Commun. 8, 15000 (2017).
Groven, R. V. M., van Koll, J., Poeze, M., Blokhuis, T. J. & van Griensven, M. miRNAs related to different processes of fracture healing: an integrative overview. Front. Surg. 8, 786564 (2021).
Pelozin, B. R. A., Soci, U. P. R., Gomes, J. L. P., Oliveira, E. M. & Fernandes, T. mTOR signaling-related microRNAs as cardiac hypertrophy modulators in high-volume endurance training. J. Appl. Physiol. 132, 126–139 (2022).
Wu, X. et al. ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity. Mol. Ther. 30, 400–414 (2022).
Pons-Espinal, M. et al. MiR-135a-5p is critical for exercise-induced adult neurogenesis. Stem Cell Rep. 12, 1298–1312 (2019).
Liu, G., Detloff, M. R., Miller, K. N., Santi, L. & Houle, J. D. Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp. Neurol. 233, 447–456 (2012).
Bonilauri, B. & Dallagiovanna, B. Long non-coding RNAs are differentially expressed after different exercise training programs. Front. Physiol. 11, 567614 (2020).
Li, Y., Chen, X., Sun, H. & Wang, H. Long non-coding RNAs in the regulation of skeletal myogenesis and muscle diseases. Cancer Lett. 417, 58–64 (2018).
Wohlwend, M. et al. The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging. Sci. Transl. Med. 13, c7367 (2021).
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).
Li, H. et al. lncExACT1 and DCHS2 regulate physiological and pathological cardiac growth. Circulation 145, 1218–1233 (2022).
Statello, L., Guo, C., Chen, L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).
Vincent, E. E. et al. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene 34, 3627–3639 (2015).
Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).
Ehrenborg, E. & Krook, A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor δ. Pharmacol. Rev. 61, 373–393 (2009).
Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem. Soc. Trans. 39, 1–13 (2011).
Višnjić, D., Lalić, H., Dembitz, V., Tomić, B. & Smoljo, T. AICAr, a widely used AMPK activator with important AMPK-independent effects: a systematic review. Cells 10, 1095 (2021).
Chiang, C. et al. Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-κB signaling. Oncotarget 8, 20706–20718 (2017).
Mallik, R. & Chowdhury, T. A. Metformin in cancer. Diabetes Res. Clin. Pract. 143, 409–419 (2018).
Ouchi, N., Shibata, R. & Walsh, K. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ. Res. 96, 838–846 (2005).
Zibrova, D. et al. GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. Biochem. J. 474, 983–1001 (2017).
Kobilo, T., Yuan, C. & van Praag, H. Endurance factors improve hippocampal neurogenesis and spatial memory in mice. Learn. Mem. 18, 103–107 (2011).
Guerrieri, D. & van Praag, H. Exercise-mimetic AICAR transiently benefits brain function. Oncotarget 6, 18293–18313 (2015).
Wrann, C. D. et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 18, 649–659 (2013).
Giaccari, A., Solini, A., Frontoni, S. & Del Prato, S. Metformin benefits: another example for alternative energy substrate mechanism? Diabetes Care 44, 647–654 (2021).
Liu, Y., Tang, G., Zhang, Z., Wang, Y. & Yang, G. Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion. Neurosci. Lett. 579, 46–51 (2014).
Zhu, X. et al. Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis. Aging 12, 17845–17862 (2020).
DiTacchio, K. A., Heinemann, S. F. & Dziewczapolski, G. Metformin treatment alters memory function in a mouse model of Alzheimer’s disease. J. Alzheimers Dis. 44, 43–48 (2015).
Stunes, A. K. et al. Skeletal effects of plyometric exercise and metformin in ovariectomized rats. Bone 132, 115193 (2020).
Chandrashekar, P. et al. Inactivation of PPARβ/δ adversely affects satellite cells and reduces postnatal myogenesis. Am. J. Physiol. Endocrinol. Metab. 309, E122–E131 (2015).
Angione, A. R., Jiang, C., Pan, D., Wang, Y. & Kuang, S. PPARδ regulates satellite cell proliferation and skeletal muscle regeneration. Skelet. Muscle 1, 33 (2011).
Nahlé, Z. et al. CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPARδ/β-mediated adaptation to metabolic stress. J. Biol. Chem. 283, 14317–14326 (2008).
Phua, W. W. T. et al. PPARβ/δ agonism upregulates Forkhead Box A2 to reduce inflammation in C2C12 myoblasts and in skeletal muscle. Int. J. Mol. Sci. 21, 1747 (2020).
Gaudel, C., Schwartz, C., Giordano, C., Abumrad, N. A. & Grimaldi, P. A. Pharmacological activation of PPARβ promotes rapid and calcineurin-dependent fiber remodeling and angiogenesis in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 295, E297–E304 (2008).
Wagner, N. et al. Peroxisome proliferator-activated receptor β stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin. Cardiovasc. Res. 83, 61–71 (2009).
Strosznajder, A. K., Wójtowicz, S., Jeżyna, M. J., Sun, G. Y. & Strosznajder, J. B. Recent insights on the role of PPAR-β/δ in neuroinflammation and neurodegeneration, and its potential target for therapy. Neuromol. Med. 23, 86–98 (2021).
Chamberlain, S., Gabriel, H., Strittmatter, W. & Didsbury, J. An exploratory phase IIa study of the PPAR delta/gamma agonist T3D-959 assessing metabolic and cognitive function in subjects with mild to moderate Alzheimer’s disease. J. Alzheimers Dis. 73, 1085–1103 (2020).
Xu, X. et al. Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats. Cardiovasc. Res. 78, 523–532 (2008).
Tawfik, V. L. et al. Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration. J. Physiol. 598, 317–329 (2020).
Bostrom, P. et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
Ma, Y. et al. Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells. FASEB J. 32, 5813–5823 (2018).
Qiao, X. et al. Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Sci. Rep. 6, 18732 (2016).
Chen, Z. et al. Recombinant irisin prevents the reduction of osteoblast differentiation induced by stimulated microgravity through increasing β-Catenin expression. Int. J. Mol. Sci. 21, 1259 (2020).
Kim, H. et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175, 1756–1768 (2018).
Jodeiri Farshbaf, M. & Alviña, K. Multiple roles in neuroprotection for the exercise derived myokine irisin. Front. Aging Neurosci. 13, 649929 (2021).
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).
Waseem, R. et al. FNDC5/irisin: physiology and pathophysiology. Molecules 27, 1118 (2022).
Huang, S., Yang, S., Lo, J., Wu, S. & Tai, M. Irisin gene delivery ameliorates burn-induced sensory and motor neuropathy. Int. J. Mol. Sci. 21, 7798 (2020).
Garekani, E. T., Mohebbi, H., Kraemer, R. R. & Fathi, R. Exercise training intensity/volume affects plasma and tissue adiponectin concentrations in the male rat. Peptides 32, 1008–1012 (2011).
Zeng, Q. et al. Effects of exercise on adiponectin and adiponectin receptor levels in rats. Life Sci. 80, 454–459 (2007).
Inoue, A. et al. Exercise restores muscle stem cell mobilization, regenerative capacity and muscle metabolic alterations via adiponectin/AdipoR1 activation in SAMP10 mice. J. Cachexia Sarcopenia Muscle 8, 370–385 (2017).
Wang, P. et al. Potential involvement of adiponectin signaling in regulating physical exercise-elicited hippocampal neurogenesis and dendritic morphology in stressed mice. Front. Cell. Neurosci. 14, 189 (2020).
You, J. et al. Role of adiponectin-Notch pathway in cognitive dysfunction associated with depression and in the therapeutic effect of physical exercise. Aging Cell 20, e13387 (2021).
Lee, T. H. et al. Chronic AdipoRon treatment mimics the effects of physical exercise on restoring hippocampal neuroplasticity in diabetic mice. Mol. Neurobiol. 58, 4666–4681 (2021).
Li, A., Yau, S. Y., Machado, S., Yuan, T. F. & So, K. F. Adult neurogenic and antidepressant effects of adiponectin: a potential replacement for exercise? CNS Neurol. Disord. Drug Targets 14, 1129–1144 (2015).
Pedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).
Peake, J. M., Della, G. P., Suzuki, K. & Nieman, D. C. Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects. Exerc. Immunol. Rev. 21, 8–25 (2015).
Reihmane, D. & Dela, F. Interleukin-6: possible biological roles during exercise. Eur. J. Sport Sci. 14, 242–250 (2014).
Storer, M. A. et al. Interleukin-6 regulates adult neural stem cell numbers during normal and abnormal post-natal development. Stem Cell Rep. 10, 1464–1480 (2018).
Cox, A. A. et al. Low-dose pulsatile interleukin-6 as a treatment option for diabetic peripheral neuropathy. Front. Endocrinol. 8, 89 (2017).
Schmitt, C., Kuhn, B., Zhang, X., Kivitz, A. J. & Grange, S. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin. Pharmacol. Ther. 89, 735–740 (2011).
Wedell-Neergaard, A. 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 (2019).
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).
Furuichi, Y., Manabe, Y., Takagi, M., Aoki, M. & Fujii, N. L. Evidence for acute contraction-induced myokine secretion by C2C12 myotubes. PLoS ONE 13, e206146 (2018).
O. Leary, M. F., Wallace, G. R., Bennett, A. J., Tsintzas, K. & Jones, S. W. IL-15 promotes human myogenesis and mitigates the detrimental effects of TNFα on myotube development. Sci. Rep. 7, 12997 (2017).
Yoshida, S. et al. Interleukin‐15 receptor subunit alpha regulates interleukin‐15 localization and protein expression in skeletal muscle cells. Exp. Physiol. 107, 222–232 (2022).
Wong, W., Crane, E. D., Kuo, Y., Kim, A. & Crane, J. D. The exercise cytokine interleukin-15 rescues slow wound healing in aged mice. J. Biol. Chem. 294, 20024–20038 (2019).
Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).
Muñoz-Espín, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).
Calcinotto, A. et al. Cellular senescence: aging, cancer, and injury. Physiol. Rev. 99, 1047–1078 (2019).
De la Rosa, A. et al. Physical exercise in the prevention and treatment of Alzheimer’s disease. J. Sport Health Sci. 9, 394–404 (2020).
Liang, Y. et al. All roads lead to Rome-a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer’s disease. Neural Regen. Res. 17, 1210–1227 (2022).
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).
Sujkowski, A., Hong, L., Wessells, R. J. & Todi, S. V. The protective role of exercise against age-related neurodegeneration. Ageing Res. Rev. 74, 101543 (2022).
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).
Watson, S. L. et al. High-intensity resistance and impact training improves bone mineral density and physical function in postmenopausal women with osteopenia and osteoporosis: the LIFTMOR randomized controlled trial. J. Bone Miner. Res. 33, 211–220 (2018).
Anupama, D. S., Norohna, J. A., Acharya, K. K., Ravishankar & George, A. Effect of exercise on bone mineral density and quality of life among postmenopausal women with osteoporosis without fracture: a systematic review. Int. J. Orthop. Trauma Nurs. 39, 100796 (2020).
Martyn-St James, M. & Carroll, S. Meta-analysis of walking for preservation of bone mineral density in postmenopausal women. Bone 43, 521–531 (2008).
Ma, D., Wu, L. & He, Z. Effects of walking on the preservation of bone mineral density in perimenopausal and postmenopausal women: a systematic review and meta-analysis. Menopause 20, 1216–1226 (2013).
Cruz-Jentoft, A. J. et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48, 16–31 (2019).
Capelli, C., Rittveger, J., Bruseghini, P., Calabria, E. & Tam, E. Maximal aerobic power and anaerobic capacity in cycling across the age spectrum in male master athletes. Eur. J. Appl. Physiol. 116, 1395–1410 (2016).
Landi, F., Marzetti, E., Martone, A. M., Bernabei, R. & Onder, G. Exercise as a remedy for sarcopenia. Curr. Opin. Clin. Nutr. 17, 25–31 (2013).
Peterson, M. D., Sen, A. & Gordon, P. M. Influence of resistance exercise on lean body mass in aging adults: a meta-analysis. Med. Sci. Sports Exerc. 43, 249–258 (2011).
Giallauria, F., Cittadini, A., Smart, N. A. & Vigorito, C. Resistance training and sarcopenia. Monaldi Arch. Chest Dis. 84, 51–53 (2016).
Papa, E. V., Dong, X. & Hassan, M. Resistance training for activity limitations in older adults with skeletal muscle function deficits: a systematic review. Clin. Interv. Aging 12, 955–961 (2017).
Joanisse, S. et al. Exercise conditioning in old mice improves skeletal muscle regeneration. FASEB J. 30, 3256–3268 (2016).
Leenders, M. et al. Elderly men and women benefit equally from prolonged resistance-type exercise training. J. Gerontol. A Biol. Sci. Med. Sci. 68, 769–779 (2013).
Cisterna, B. et al. Adapted physical exercise enhances activation and differentiation potential of satellite cells in the skeletal muscle of old mice. J. Anat. 228, 771–783 (2016).
Zacharewicz, E. et al. Identification of MicroRNAs linked to regulators of muscle protein synthesis and regeneration in young and old skeletal muscle. PLoS ONE 9, e114009 (2014).
Arnold, M. J. & Moody, A. L. Common running injuries: evaluation and management. Am. Fam. Physician 97, 510–516 (2018).
Fagher, K. & Lexell, J. Sports-related injuries in athletes with disabilities. Scand. J. Med. Sci. Sports 24, e320–e331 (2014).
Murphy, C., O. Connell, J. E., Kearns, G. & Stassen, L. Sports-related maxillofacial injuries. J. Craniofac. Surg. 26, 2120–2123 (2015).
Pierpoint, L. A. & Collins, C. Epidemiology of sport-related concussion. Clin. Sports Med. 40, 1–18 (2021).
Elliott, A. D., Linz, D., Verdicchio, C. V. & Sanders, P. Exercise and atrial fibrillation: prevention or causation? Heart Lung Circ. 27, 1078–1085 (2018).
O’Keefe, E. L., Torres-Acosta, N., O’Keefe, J. H. & Lavie, C. J. Training for longevity: the reverse J-Curve for exercise. Mo. Med. 117, 355–361 (2020).
Dockerill, C., Lapidaire, W., Lewandowski, A. J. & Leeson, P. Cardiac remodelling and exercise: what happens with ultra-endurance exercise? Eur. J. Prev. Cardiol. 27, 1464–1466 (2020).
Geesmann, B., Gibbs, J. C., Mester, J. & Koehler, K. Association between energy balance and metabolic hormone suppression during ultraendurance exercise. Int. J. Sports Physiol. Perform. 12, 984–989 (2017).
Turner, J. E., Bennett, S. J., Bosch, J. A., Griffiths, H. R. & Aldred, S. Ultra-endurance exercise: unanswered questions in redox biology and immunology. Biochem. Soc. Trans. 42, 989–995 (2014).
Seo, M. et al. Effects of 16 weeks of resistance training on muscle quality and muscle growth factors in older adult women with sarcopenia: a randomized controlled trial. Int. J. Environ. Res. Public Health 18, 6762 (2021).
Kemmler, W. et al. Effects of high‐intensity resistance training on osteopenia and sarcopenia parameters in older men with osteosarcopenia—one‐year results of the randomized controlled Franconian Osteopenia and Sarcopenia Trial (FrOST). J. Bone Miner. Res. 35, 1634–1644 (2020).
Aamann, L. et al. Resistance training increases muscle strength and muscle size in patients with liver cirrhosis. Clin. Gastroenterol. Hepatol. 18, 1179–1187 (2020).
Lichtenberg, T., von Stengel, S., Sieber, C. & Kemmler, W. The favorable effects of a high-intensity resistance training on sarcopenia in older community-dwelling men with osteosarcopenia: the randomized controlled FrOST study. Clin. Interv. Aging 14, 2173–2186 (2019).
FilipoviC, T. N. et al. A 12-week exercise program improves functional status in postmenopausal osteoporotic women: randomized controlled study. Eur. J. Phys. Rehabil. Med. 57, 120–130 (2021).
Harding, A. T. et al. Exploring thoracic kyphosis and incident fracture from vertebral morphology with high-intensity exercise in middle-aged and older men with osteopenia and osteoporosis: a secondary analysis of the LIFTMOR-M trial. Osteoporos. Int. 32, 451–465 (2021).
Harding, A. T. et al. Effects of supervised high-intensity resistance and impact training or machine-based isometric training on regional bone geometry and strength in middle-aged and older men with low bone mass: the LIFTMOR-M semi-randomised controlled trial. Bone 136, 115362 (2020).
Otero, M., Esain, I., Gonzalez-Suarez, A. M. & Gil, S. M. The effectiveness of a basic exercise intervention to improve strength and balance in women with osteoporosis. Clin. Interv. Aging 12, 505–513 (2017).
Pandey, A. et al. Frailty status modifies the efficacy of exercise training among patients with chronic heart failure and reduced ejection fraction: an analysis from the HF-ACTION trial. Circulation 146, 80–90 (2022).
Hieda, M. et al. One-year committed exercise training reverses abnormal left ventricular myocardial stiffness in patients with stage B heart failure with preserved ejection fraction. Circulation 144, 934–946 (2021).
Liu-Ambrose, T. et al. Aerobic exercise and vascular cognitive impairment. Neurology 87, 2082–2090 (2016).
Bo, W. et al. Effects of combined intervention of physical exercise and cognitive training on cognitive function in stroke survivors with vascular cognitive impairment: a randomized controlled trial. Clin. Rehabil. 33, 54–63 (2019).
Nave, A. H. et al. Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial. BMJ 366, l5101 (2019).
Sobol, N. A. et al. Effect of aerobic exercise on physical performance in patients with Alzheimer’s disease. Alzheimers Dement. 12, 1207–1215 (2016).
Lautenschlager, N. T. et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease. JAMA 300, 1027–1037 (2008).
Lamb, S. E. et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ 361, k1675 (2018).