Does Exercise Regulate Autophagy in Humans? A Systematic Review and Meta-Analysis

References

• Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27–24.
   PubMed Web of Science ®Google Scholar
• Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 2021; 17:1–382.
   PubMed Web of Science ®Google Scholar
• Pyo J-O, Yoo S-M, Ahn H-H, Nah J, Hong S-H, Kam T-I, Jung S, Jung Y-K. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 2013; 4:2300.
   PubMed Web of Science ®Google Scholar
• Fernández ÁF, Sebti S, Wei Y, Zou Z, Shi M, McMillan KL, He C, Ting T, Liu Y, Chiang W-C, et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 2018; 558:136–40.
   PubMed Web of Science ®Google Scholar
• Levine B. Cell biology: autophagy and cancer. Nature2007; 446:745–7.
   Google Scholar
• Zhou B, Kreuzer J, Kumsta C, Wu L, Kamer KJ, Cedillo L, Zhang Y, Li S, Kacergis MC, Webster CM, et al. Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension. Cell 2019; 177:299–314.e16.
   PubMed Web of Science ®Google Scholar
• Ulgherait M, Midoun AM, Park SJ, Gatto JA, Tener SJ, Siewert J, Klickstein N, Canman JC, Ja WW, Shirasu-Hiza M. Circadian autophagy drives iTRF-mediated longevity. Nature 2021; 598:353–8.
   PubMed Web of Science ®Google Scholar
• Konings E, Timmers S, Boekschoten M V, Goossens GH, Jocken JW, Afman LA, Müller M, Schrauwen P, Mariman EC, Blaak EE. The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes (Lond) 2014; 38:470–3.
   PubMed Web of Science ®Google Scholar
• Halling JF, Pilegaard H. Autophagy-Dependent Beneficial Effects of Exercise. Cold Spring Harb Perspect Med 2017; 7.
   Google Scholar
• He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012; 481:511–5.
   PubMed Web of Science ®Google Scholar
• He C, Sumpter Rhea J, Levine B. Exercise induces autophagy in peripheral tissues and in the brain. Autophagy 2012; 8:1548–51.
   PubMed Web of Science ®Google Scholar
• Organization WH. Global health risks: mortality and burden of disease attributable to selected major risks. World Health Organization; 2009.
   Google Scholar
• Drummond MJ, Addison O, Brunker L, Hopkins PN, McClain DA, LaStayo PC, Marcus RL. Downregulation of E3 ubiquitin ligases and mitophagy-related genes in skeletal muscle of physically inactive, frail older women: a cross-sectional comparison. J Gerontol A Biol Sci Med Sci 2014; 69:1040–8.
   PubMed Web of Science ®Google Scholar
• Lira VA, Okutsu M, Zhang M, Greene NP, Laker RC, Breen DS, Hoehn KL, Yan Z. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J Off Publ Fed Am Soc Exp Biol 2013; 27:4184–93.
   PubMed Web of Science ®Google Scholar
• Codina-Martínez H, Fernández-García B, Díez-Planelles C, Fernández ÁF, Higarza SG, Fernández-Sanjurjo M, Díez-Robles S, Iglesias-Gutiérrez E, Tomás-Zapico C. Autophagy is required for performance adaptive response to resistance training and exercise-induced adult neurogenesis. Scand J Med Sci Sports 2020; 30:238–53.
   PubMed Web of Science ®Google Scholar
• Lo Verso F, Carnio S, Vainshtein A, Sandri M. Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity. Autophagy 2014; 10:1883–94.
   PubMed Web of Science ®Google Scholar
• Guan Y, Drake JC, Yan Z. Exercise-Induced Mitophagy in Skeletal Muscle and Heart. Exerc Sport Sci Rev 2019; 47:151–6.
   PubMed Web of Science ®Google Scholar
• Kang E-B, Cho J-Y. Effect of treadmill exercise on PI3K/AKT/mTOR, autophagy, and Tau hyperphosphorylation in the cerebral cortex of NSE/htau23 transgenic mice. J Exerc Nutr Biochem 2015; 19:199–209.
   PubMedGoogle Scholar
• Rocchi A, Yamamoto S, Ting T, Fan Y, Sadleir K, Wang Y, Zhang W, Huang S, Levine B, Vassar R, et al. A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer’s disease. PLoS Genet 2017; 13:e1006962.
   PubMed Web of Science ®Google Scholar
• Campos JC, Queliconi BB, Bozi LHM, Bechara LRG, Dourado PMM, Andres AM, Jannig PR, Gomes KMS, Zambelli VO, Rocha-Resende C, et al. Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure. Autophagy 2017; 13:1304–17.
   PubMed Web of Science ®Google Scholar
• Arribat Y, Broskey NT, Greggio C, Boutant M, Conde Alonso S, Kulkarni SS, Lagarrigue S, Carnero EA, Besson C, Cantó C, et al. Distinct patterns of skeletal muscle mitochondria fusion, fission and mitophagy upon duration of exercise training. Acta Physiol (Oxf) 2019; 225:e13179.
   PubMed Web of Science ®Google Scholar
• Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H. Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep 2018; 6:e13651.
   PubMed Web of Science ®Google Scholar
• Dokladny K, Zuhl MN, Mandell M, Bhattacharya D, Schneider S, Deretic V, Moseley PL. Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy. J Biol Chem 2013; 288:14959–72.
   PubMed Web of Science ®Google Scholar
• Escobar KA, Welch AM, Wells A, Fennel Z, Nava R, Li Z, Moriarty TA, Nitta CH, Zuhl MN, VanDusseldorp TA. Autophagy response to acute high-intensity interval training and moderate-intensity continuous training is dissimilar in skeletal muscle and peripheral blood mononuclear cells and is influenced by sex. Hum Nutr Metab 2021; 23:200118.
   Google Scholar
• Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High-intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiol (Oxf) 2019; 225:e13208.
   PubMed Web of Science ®Google Scholar
• Tam BT, Siu PM. Autophagic cellular responses to physical exercise in skeletal muscle. Sports Med 2014; 44:625–40.
   PubMed Web of Science ®Google Scholar
• Vainshtein A, Hood DA. The regulation of autophagy during exercise in skeletal muscle. J Appl Physiol 2016; 120:664–73.
   PubMed Web of Science ®Google Scholar
• Martin-Rincon M, Morales-Alamo D, Calbet JAL. Exercise-mediated modulation of autophagy in skeletal muscle. Scand J Med Sci Sports 2018; 28:772–81.
   PubMed Web of Science ®Google Scholar
• Liang J, Zeng Z, Zhang Y, Chen N. Regulatory role of exercise-induced autophagy for sarcopenia. Exp Gerontol 2020; 130:110789.
   PubMed Web of Science ®Google Scholar
• Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015; 350:g7647.
   PubMed Web of Science ®Google Scholar
• Higgins JP. Cochrane handbook for systematic reviews of interventions. Version 5.1. 0 [updated March 2011]. The Cochrane Collaboration. www.cochrane-handbook.org 2011;
   Google Scholar
• Rohatgi A. WebPlotDigitizer. URL http://arohatgi. info. WebPlotDigitizer/app 2011;
   Google Scholar
• Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21:1539–58.
   PubMed Web of Science ®Google Scholar
• Hentilä J, Ahtiainen JP, Paulsen G, Raastad T, Häkkinen K, Mero AA, Hulmi JJ. Autophagy is induced by resistance exercise in young men, but unfolded protein response is induced regardless of age. Acta Physiol (Oxf) 2018; 224:e13069.
   PubMed Web of Science ®Google Scholar
• Huang C-J, Rodriguez AL, Visavadiya NP, Fico BG, Slusher AL, Ferrandi PJ, Whitehurst M. An exploratory investigation of apoptotic and autophagic responses in peripheral blood mononuclear cells following maximal aerobic exercise in obese individuals. Arch Physiol Biochem 2019;:1–8.
   Web of Science ®Google Scholar
• Jamart C, Francaux M, Millet GY, Deldicque L, Frère D, Féasson L. Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running. J Appl Physiol 2012; 112:1529–37.
   PubMed Web of Science ®Google Scholar
• Kruse R, Pedersen AJT, Kristensen JM, Petersson SJ, Wojtaszewski JFP, Højlund K. Intact initiation of autophagy and mitochondrial fission by acute exercise in skeletal muscle of patients with Type 2 diabetes. Clin Sci (Lond) 2017; 131:37–47.
   PubMed Web of Science ®Google Scholar
• Masschelein E, Van Thienen R, D’Hulst G, Hespel P, Thomis M, Deldicque L. Acute environmental hypoxia induces LC3 lipidation in a genotype-dependent manner. FASEB J Off Publ Fed Am Soc Exp Biol 2014; 28:1022–34.
   PubMed Web of Science ®Google Scholar
• Mazo CE, D’Lugos AC, Sweeney KR, Haus JM, Angadi SS, Carroll CC, Dickinson JM. The effects of acute aerobic and resistance exercise on mTOR signaling and autophagy markers in untrained human skeletal muscle. Eur J Appl Physiol 2021; 121:2913–24.
   PubMed Web of Science ®Google Scholar
• McCormick JJ, King KE, Dokladny K, Mermier CM. Effect of Acute Aerobic Exercise and Rapamycin Treatment on Autophagy in Peripheral Blood Mononuclear Cells of Adults With Prediabetes. Can J diabetes 2019; 43:457–63.
   PubMed Web of Science ®Google Scholar
• Mejías-Peña Y, Estébanez B, Rodriguez-Miguelez P, Fernandez-Gonzalo R, Almar M, de Paz JA, González-Gallego J, Cuevas MJ. Impact of resistance training on the autophagy-inflammation-apoptosis crosstalk in elderly subjects. Aging (Albany NY) 2017; 9:408–18.
   PubMedGoogle Scholar
• Mejías-Peña Y, Rodriguez-Miguelez P, Fernandez-Gonzalo R, Martínez-Flórez S, Almar M, de Paz JA, Cuevas MJ, González-Gallego J. Effects of aerobic training on markers of autophagy in the elderly. Age (Dordr) 2016; 38:33.
   PubMedGoogle Scholar
• Moberg M, Hendo G, Jakobsson M, Mattsson CM, Ekblom-Bak E, Flockhart M, Pontén M, Söderlund K, Ekblom B. Increased autophagy signaling but not proteasome activity in human skeletal muscle after prolonged low-intensity exercise with negative energy balance. Physiol Rep 2017; 5.
   Google Scholar
• Schwalm C, Jamart C, Benoit N, Naslain D, Prémont C, Prévet J, Van Thienen R, Deldicque L, Francaux M. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J Off Publ Fed Am Soc Exp Biol 2015; 29:3515–26.
   PubMed Web of Science ®Google Scholar
• Schwalm C, Deldicque L, Francaux M. Lack of Activation of Mitophagy during Endurance Exercise in Human. Med Sci Sports Exerc 2017; 49:1552–61.
   PubMed Web of Science ®Google Scholar
• Tachtsis B, Smiles WJ, Lane SC, Hawley JA, Camera DM. Acute Endurance Exercise Induces Nuclear p53 Abundance in Human Skeletal Muscle. Front Physiol 2016; 7:144.
   PubMed Web of Science ®Google Scholar
• Ulbricht A, Gehlert S, Leciejewski B, Schiffer T, Bloch W, Höhfeld J. Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy 2015; 11:538–46.
   PubMed Web of Science ®Google Scholar
• Botella J, Jamnick NA, Granata C, Genders AJ, Perri E, Jabar T, Garnham A, Lazarou M, Bishop DJ. Exercise and Training Regulation of Autophagy Markers in Human and Rat Skeletal Muscle. Int J Mol Sci 2022; 23.
   PubMedGoogle Scholar
• Moberg M, Apró W, Horwath O, van Hall G, Blackwood SJ, Katz A. Acute normobaric hypoxia blunts contraction-mediated mTORC1- and JNK-signaling in human skeletal muscle. Acta Physiol (Oxf) 2022; 234:e13771.
   PubMed Web of Science ®Google Scholar
• Kröpfl JM, Morandi C, Gasser BA, Schoch R, Schmidt-Trucksäss A, Brink M. Lymphocytes are less sensitive to autophagy than monocytes during fasting and exercise conditions. Apoptosis 2022; 27:730–9.
   PubMed Web of Science ®Google Scholar
• Brinkmann C, Przyklenk A, Metten A, Schiffer T, Bloch W, Brixius K, Gehlert S. Influence of endurance training on skeletal muscle mitophagy regulatory proteins in type 2 diabetic men. Endocr Res 2017; 42:325–30.
   PubMed Web of Science ®Google Scholar
• Fritzen AM, Madsen AB, Kleinert M, Treebak JT, Lundsgaard A-M, Jensen TE, Richter EA, Wojtaszewski J, Kiens B, Frøsig C. Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation. J Physiol 2016; 594:745–61.
   PubMed Web of Science ®Google Scholar
• Fry CS, Drummond MJ, Glynn EL, Dickinson JM, Gundermann DM, Timmerman KL, Walker DK, Volpi E, Rasmussen BB. Skeletal muscle autophagy and protein breakdown following resistance exercise are similar in younger and older adults. J Gerontol A Biol Sci Med Sci 2013; 68:599–607.
   PubMed Web of Science ®Google Scholar
• Glynn EL, Fry CS, Drummond MJ, Dreyer HC, Dhanani S, Volpi E, Rasmussen BB. Muscle protein breakdown has a minor role in the protein anabolic response to essential amino acid and carbohydrate intake following resistance exercise. Am J Physiol Regul Integr Comp Physiol 2010; 299:R533–40.
   PubMed Web of Science ®Google Scholar
• Hentilä J, Hulmi JJ, Laakkonen EK, Ahtiainen JP, Suominen H, Korhonen MT. Sprint and Strength Training Modulates Autophagy and Proteostasis in Aging Sprinters. Med Sci Sports Exerc 2020; 52:1948–59.
   PubMed Web of Science ®Google Scholar
• Salminen A, Vihko V. Autophagic response to strenuous exercise in mouse skeletal muscle fibers. Virchows Arch B Cell Pathol Incl Mol Pathol 1984; 45:97–106.
   PubMed Web of Science ®Google Scholar
• Liu H, Lei H, Shi Y, Wang J-J, Chen N, Li Z-H, Chen Y-F, Ye Q-F, Yang Y. Autophagy inhibitor 3-methyladenine alleviates overload-exercise-induced cardiac injury in rats. Acta Pharmacol Sin 2017; 38:990–7.
   PubMed Web of Science ®Google Scholar
• Luo L, Lu A-M, Wang Y, Hong A, Chen Y, Hu J, Li X, Qin Z-H. Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, Akt/mTOR and Akt/FOXO3a signaling in aged rats. Exp Gerontol 2013; 48:427–36.
   PubMed Web of Science ®Google Scholar
• White Z, Terrill J, White RB, McMahon C, Sheard P, Grounds MD, Shavlakadze T. Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice. Skelet Muscle 2016; 6:45.
   PubMed Web of Science ®Google Scholar
• Cui D, Drake JC, Wilson RJ, Shute RJ, Lewellen B, Zhang M, Zhao H, Sabik OL, Onengut S, Berr SS, et al. A novel voluntary weightlifting model in mice promotes muscle adaptation and insulin sensitivity with simultaneous enhancement of autophagy and mTOR pathway. FASEB J Off Publ Fed Am Soc Exp Biol 2020; 34:7330–44.
   PubMed Web of Science ®Google Scholar
• Kim YA, Kim YS, Song W. Autophagic response to a single bout of moderate exercise in murine skeletal muscle. J Physiol Biochem 2012; 68:229–35.
   PubMed Web of Science ®Google Scholar
• Fuller KNZ, Thyfault JP. Barriers in translating preclinical rodent exercise metabolism findings to human health. J Appl Physiol 2021; 130:182–92.
   PubMed Web of Science ®Google Scholar
• Deldicque L, Theisen D, Francaux M. Regulation of mTOR by amino acids and resistance exercise in skeletal muscle. Eur J Appl Physiol 2005; 94:1–10.
   PubMed Web of Science ®Google Scholar
• Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M. Autophagy is required to maintain muscle mass. Cell Metab 2009; 10:507–15.
   PubMed Web of Science ®Google Scholar
• Pagano AF, Py G, Bernardi H, Candau RB, Sanchez AMJ. Autophagy and protein turnover signaling in slow-twitch muscle during exercise. Med Sci Sports Exerc 2014; 46:1314–25.
   PubMed Web of Science ®Google Scholar
• Hargreaves M, Spriet LL. Skeletal muscle energy metabolism during exercise. Nat Metab 2020; 2:817–28.
   PubMedGoogle Scholar
• Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 2013; 17:162–84.
   PubMed Web of Science ®Google Scholar
• Cassidy S, Thoma C, Houghton D, Trenell MI. High-intensity interval training: a review of its impact on glucose control and cardiometabolic health. Diabetologia 2017; 60:7–23.
   PubMed Web of Science ®Google Scholar
• Wang L, Wang J, Cretoiu D, Li G, Xiao J. Exercise-mediated regulation of autophagy in the cardiovascular system. J Sport Heal Sci 2020; 9:203–10.
   PubMed Web of Science ®Google Scholar