{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:06:57Z","timestamp":1785928017210,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003981","name":"Agenzia Spaziale Italiana","doi-asserted-by":"publisher","award":["ASI N. 2019-11-U.0."],"award-info":[{"award-number":["ASI N. 2019-11-U.0."]}],"id":[{"id":"10.13039\/501100003981","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A large set of FoxOs-dependent genes play a primary role in controlling muscle mass during hindlimb unloading. Mitochondrial dysfunction can modulate such a process. We hypothesized that endurance exercise before disuse can protect against disuse-induced muscle atrophy by enhancing peroxisome proliferator-activated receptor-\u03b3 coactivator-1\u03b1 (PGC1\u03b1) expression and preventing mitochondrial dysfunction and energy-sensing AMP-activated protein kinase (AMPK) activation. We studied cross sectional area (CSA) of muscle fibers of gastrocnemius muscle by histochemistry following 1, 3, 7, and 14 days of hindlimb unloading (HU). We used Western blotting and qRT-PCR to study mitochondrial dynamics and FoxOs-dependent atrogenes\u2019 expression at 1 and 3 days after HU. Preconditioned animals were submitted to moderate treadmill exercise for 7 days before disuse. Exercise preconditioning protected the gastrocnemius from disuse atrophy until 7 days of HU. It blunted alterations in mitochondrial dynamics up to 3 days after HU and the expression of most atrogenes at 1 day after disuse. In preconditioned mice, the activation of atrogenes resumed 3 days after HU when mitochondrial dynamics, assessed by profusion and pro-fission markers (mitofusin 1, MFN1, mitofusin 2, MFN2, optic atrophy 1, OPA1, dynamin related protein 1, DRP1 and fission 1, FIS1), PGC1\u03b1 levels, and AMPK activation were at a basal level. Therefore, the normalization of mitochondrial dynamics and function was not sufficient to prevent atrogenes activation just a few days after HU. The time course of sirtuin 1 (SIRT1) expression and content paralleled the time course of atrogenes\u2019 expression. In conclusion, seven days of endurance exercise counteracted alterations of mitochondrial dynamics and the activation of atrogenes early into disuse. Despite the normalization of mitochondrial dynamics, the effect on atrogenes\u2019 suppression died away within 3 days of HU. Interestingly, muscle protection lasted until 7 days of HU. A longer or more intense exercise preconditioning may prolong atrogenes suppression and muscle protection.<\/jats:p>","DOI":"10.3390\/ijms23010148","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T10:16:18Z","timestamp":1640254578000},"page":"148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Exercise Preconditioning Blunts Early Atrogenes Expression and Atrophy in Gastrocnemius Muscle of Hindlimb Unloaded Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Lorenza","family":"Brocca","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maira","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Canepari","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4960-7490","authenticated-orcid":false,"given":"Roberto","family":"Bottinelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"ICS-Maugeri (IRCCS), Scientific Institute of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1653-1266","authenticated-orcid":false,"given":"Maria Antonietta","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"Interdipartimental Centre of Biology and Sport Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.clnu.2009.09.006","article-title":"Inactivity-mediated insulin resistance is associated with upregulated pro-inflammatory fatty acids in human cell membranes","volume":"29","author":"Mazzucco","year":"2010","journal-title":"Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/cphy.c110025","article-title":"Lack of exercise is a major cause of chronic diseases","volume":"2","author":"Booth","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1242\/dmm.010389","article-title":"Cellular and molecular mechanisms of muscle atrophy","volume":"6","author":"Bonaldo","year":"2013","journal-title":"Dis. Model. Mech."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/sms.12581","article-title":"Exercise as medicine-evidence for prescribing exercise as therapy in 26 different chronic diseases","volume":"25","author":"Pedersen","year":"2015","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16260","DOI":"10.1073\/pnas.0607795103","article-title":"PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription","volume":"103","author":"Sandri","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20405","DOI":"10.1073\/pnas.0911570106","article-title":"Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging","volume":"106","author":"Wenz","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1016\/j.ajpath.2011.01.005","article-title":"PGC-1\u03b1 promotes nitric oxide antioxidant defenses and inhibits FOXO signaling against cardiac cachexia in mice","volume":"178","author":"Geng","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4575","DOI":"10.1113\/jphysiol.2014.275545","article-title":"PGC1-alpha over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice","volume":"592","author":"Cannavino","year":"2014","journal-title":"J. Physiol."},{"key":"ref_9","first-page":"422","article-title":"Mitochondrial Quality Control and Muscle Mass Maintenance","volume":"6","author":"Romanello","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cell.2010.02.026","article-title":"Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations","volume":"141","author":"Chen","year":"2010","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.cmet.2015.05.007","article-title":"The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage","volume":"21","author":"Varanita","year":"2015","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1038\/s41467-019-10226-9","article-title":"DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass","volume":"10","author":"Favaro","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1113\/jphysiol.2014.286740","article-title":"The role of alterations in mitochondrial dynamics and PGC-1alpha over-expression in fast muscle atrophy following hindlimb unloading","volume":"593","author":"Cannavino","year":"2015","journal-title":"J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Safdar, A., Abadi, A., Akhtar, M., Hettinga, B.P., and Tarnopolsky, M.A. (2009). miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl\/6J male mice. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005610"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1152\/japplphysiol.00765.2003","article-title":"PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle","volume":"96","author":"Norrbom","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.2337\/diabetes.52.12.2874","article-title":"Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle","volume":"52","author":"Russell","year":"2003","journal-title":"Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101462","DOI":"10.1016\/j.redox.2020.101462","article-title":"Mechanisms of exercise-induced preconditioning in skeletal muscles","volume":"35","author":"Powers","year":"2020","journal-title":"Redox. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1152\/japplphysiol.00137.2018","article-title":"Exercise preconditioning diminishes skeletal muscle atrophy after hindlimb suspension in mice","volume":"125","author":"Theilen","year":"2018","journal-title":"J. Appl. Physiol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1748-1716.2009.01984.x","article-title":"Protective effects of exercise preconditioning on hindlimb unloading-induced atrophy of rat soleus muscle","volume":"197","author":"Fujino","year":"2009","journal-title":"Acta Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.exger.2019.04.010","article-title":"Exercise preconditioning attenuates hind limb unloading-induced gastrocnemius muscle atrophy possibly via the HDAC4\/Gadd45 axis in old rats","volume":"122","author":"Yoshihara","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1152\/physiol.00041.2007","article-title":"Signaling in muscle atrophy and hypertrophy","volume":"23","author":"Sandri","year":"2008","journal-title":"Physiology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1139\/H09-137","article-title":"Little change in markers of protein breakdown and oxidative stress in humans in immobilization-induced skeletal muscle atrophy","volume":"35","author":"Glover","year":"2010","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1126\/science.1065874","article-title":"Identification of ubiquitin ligases required for skeletal muscle atrophy","volume":"294","author":"Bodine","year":"2001","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.semcdb.2015.11.002","article-title":"Protein breakdown in cancer cachexia","volume":"54","author":"Sandri","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.1038\/ncomms7670","article-title":"Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy","volume":"6","author":"Milan","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1113\/JP273097","article-title":"FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension","volume":"595","author":"Brocca","year":"2017","journal-title":"J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1038\/emboj.2010.60","article-title":"Mitochondrial fission and remodelling contributes to muscle atrophy","volume":"29","author":"Romanello","year":"2010","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.1094637","article-title":"Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase","volume":"303","author":"Brunet","year":"2004","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4890","DOI":"10.1128\/MCB.00180-10","article-title":"Stimulation of Sirt1-regulated FoxO protein function by the ligand-bound vitamin D receptor","volume":"30","author":"An","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1113\/expphysiol.2009.050245","article-title":"Is oxidative stress a cause or consequence of disuse muscle atrophy in mice? A proteomic approach in hindlimb-unloaded mice","volume":"95","author":"Brocca","year":"2010","journal-title":"Exp. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1113\/jphysiol.2010.188011","article-title":"Exercise intensity-dependent regulation of peroxisome proliferator-activated receptor. coactivator-1 alpha mRNA abundance is associated with differential activation of upstream signalling kinases in human skeletal muscle","volume":"588","author":"Egan","year":"2010","journal-title":"J. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.phrs.2010.01.012","article-title":"Antioxidant treatment of hindlimb-unloaded mouse counteracts fiber type transition but not atrophy of disused muscles","volume":"61","author":"Desaphy","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/mus.23753","article-title":"Longitudinal characterization of functional, morphologic, and biochemical adaptations in mouse skeletal muscle with hindlimb suspension","volume":"48","author":"Hanson","year":"2013","journal-title":"Muscle Nerve"},{"key":"ref_34","first-page":"140","article-title":"Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases","volume":"21","author":"Sacheck","year":"2007","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13395-016-0086-6","article-title":"The beneficial role of proteolysis in skeletal muscle growth and stress adaptation","volume":"6","author":"Bell","year":"2016","journal-title":"Skelet Muscle"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e13216","DOI":"10.1111\/apha.13216","article-title":"Exercise training remodels human skeletal muscle mitochondrial fission and fusion machinery towards a pro-elongation phenotype","volume":"225","author":"Axelrod","year":"2019","journal-title":"Acta Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/mus.23838","article-title":"Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse","volume":"48","author":"Iqbal","year":"2013","journal-title":"Muscle Nerve"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21583","DOI":"10.1074\/jbc.C700083200","article-title":"Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology","volume":"282","author":"Chang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hu, C., Huang, Y., and Li, L. (2017). Drp1-Dependent Mitochondrial Fission Plays Critical Roles in Physiological and Pathological Progresses in Mammals. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010144"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3389\/fphys.2019.00532","article-title":"Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet","volume":"10","author":"Sergi","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"C587","DOI":"10.1152\/ajpcell.00142.2011","article-title":"Posttranslational modifications control FoxO3 activity during denervation","volume":"302","author":"Bertaggia","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0092-8674(04)00126-6","article-title":"Mammalian SIRT1 represses forkhead transcription factors","volume":"116","author":"Motta","year":"2004","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/sj.emboj.7600570","article-title":"Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation","volume":"24","author":"Yang","year":"2005","journal-title":"EMBO J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"30515","DOI":"10.1074\/jbc.M113.489716","article-title":"SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth","volume":"288","author":"Lee","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_46","first-page":"1441","article-title":"HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy","volume":"127","author":"Beharry","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1152\/japplphysiol.91451.2008","article-title":"Relationship between Sirt1 expression and mitochondrial proteins during conditions of chronic muscle use and disuse","volume":"107","author":"Chabi","year":"2009","journal-title":"J. Appl. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1002\/jcp.25635","article-title":"Short- and Long-Term Hindlimb Immobilization and Reloading: Profile of Epigenetic Events in Gastrocnemius","volume":"232","author":"Gea","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"C1490","DOI":"10.1152\/ajpcell.00255.2010","article-title":"p300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle","volume":"300","author":"Senf","year":"2011","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/s41467-020-20123-1","article-title":"Mechanisms of muscle atrophy and hypertrophy: Implications in health and disease","volume":"12","author":"Sartori","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.1111\/febs.12228","article-title":"Moderate-intensity treadmill running promotes expansion of the satellite cell pool in young and old mice","volume":"280","author":"Shefer","year":"2013","journal-title":"FEBS J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/148\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:52:22Z","timestamp":1760169142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,23]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23010148"],"URL":"https:\/\/doi.org\/10.3390\/ijms23010148","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,23]]}}}