{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:01:50Z","timestamp":1792008110693,"version":"4.4.0"},"reference-count":42,"publisher":"Institute of Physiology of the Czech Academy of Sciences","issue":"1\/2024","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown. In this study, we investigated the biological mechanisms by which EMS-induced muscle contraction inhibits disuse muscle atrophy progression. Experimental animals were divided into a control group and three experimental groups: immobilized (Im; immobilization treatment), low-frequency (LF; immobilization treatment and low-frequency muscle contraction exercise), and high-frequency (HF; immobilization treatment and high-frequency muscle contraction exercise). Following the experimental period, bilateral soleus muscles were collected and analyzed. Atrogin-1 and Muscle RING finger 1 (MuRF-1) mRNA expression levels were significantly higher for the experimental groups than for the control group but were significantly lower for the HF group than for the Im group. Peroxisome proliferator-activated receptor \u03b3 coactivator-1\u03b1 (PGC-1\u03b1) mRNA and protein expression levels in the HF group were significantly higher than those in the Im group, with no significant differences compared to the Con group. Both the Forkhead box O (FoxO)\/phosphorylated FoxO and protein kinase B (AKT)\/phosphorylated AKT ratios were significantly lower for the Im group than for the control group and significantly higher for the HF group than for the Im group. These results, the suppression of atrogin-1 and MuRF-1 expression for the HF group may be due to decreased nuclear expression of FoxO by AKT phosphorylation and suppression of FoxO transcriptional activity by PGC-1\u03b1. Furthermore, the number of muscle contractions might be important for effective EMS.<\/jats:p>","DOI":"10.33549\/physiolres.935157","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T10:07:21Z","timestamp":1710151641000},"page":"105-115","source":"Crossref","is-referenced-by-count":7,"title":["Skeletal Muscle Electrical Stimulation Prevents Progression of Disuse Muscle Atrophy via Forkhead Box O Dynamics Mediated by Phosphorylated Protein Kinase B and Peroxisome Proliferator-Activated Receptor \u03b3 Coactivator-1\u03b1"],"prefix":"10.33549","author":[{"given":"A","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Miyake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Kataoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Okita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2024,3,6]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"1.\tRudrappa SS, Wilkinson DJ, Greenhaff PL, Smith K, Idris I, Atherton PJ. Human Skeletal Muscle Disuse Atrophy: Effects on Muscle Protein Synthesis, Breakdown, and Insulin Resistance-A Qualitative Review. Front Physiol 2016;7:361. https:\/\/doi.org\/10.3389\/fphys.2016.00361","DOI":"10.3389\/fphys.2016.00361"},{"key":"ref1","doi-asserted-by":"crossref","unstructured":"2.\tGraham ZA, Lavin KM, O'Bryan SM, Thalacker-Mercer AE, Buford TW, Ford KM, Broderick TJ, ET AL. Mechanisms of exercise as a preventative measure to muscle wasting. Am J Physiol Cell Physiol 2021;321:C40-C57. https:\/\/doi.org\/10.1152\/ajpcell.00056.2021","DOI":"10.1152\/ajpcell.00056.2021"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"3.\tMukund K, Subramaniam S. Skeletal muscle: A review of molecular structure and function, in health and disease. Wiley Interdiscip Rev Syst Biol Med 2020;12:e1462. https:\/\/doi.org\/10.1002\/wsbm.1462","DOI":"10.1002\/wsbm.1462"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"4.\tThomason DB, Booth FW. Atrophy of the soleus muscle by hindlimb unweighting. J Appl Physiol (1985) 1990;68:1-12. https:\/\/doi.org\/10.1152\/jappl.1990.68.1.1","DOI":"10.1152\/jappl.1990.68.1.1"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"5.\tPhillips SM, McGlory C. CrossTalk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis. J Physiol 2014;592:5341-5343. https:\/\/doi.org\/10.1113\/jphysiol.2014.273615","DOI":"10.1113\/jphysiol.2014.273615"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"6.\tAtherton PJ, Greenhaff PL, Phillips SM, Bodine SC, Adams CM, Lang CH. Control of skeletal muscle atrophy in response to disuse: clinical\/preclinical contentions and fallacies of evidence. Am J Physiol Endocrinol Metab 2016;311:E594-E604. https:\/\/doi.org\/10.1152\/ajpendo.00257.2016","DOI":"10.1152\/ajpendo.00257.2016"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"7.\tSanchez AM, Candau RB, Bernardi H. FoxO transcription factors: their roles in the maintenance of skeletal muscle homeostasis. Cell Mol Life Sci 2014;71:1657-1671. https:\/\/doi.org\/10.1007\/s00018-013-1513-z","DOI":"10.1007\/s00018-013-1513-z"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"8.\tChen K, Gao P, Li Z, Dai A, Yang M, Chen S, Su J, ET AL. Forkhead Box O Signaling Pathway in Skeletal Muscle Atrophy. Am J Pathol 2022;192:1648-1657. https:\/\/doi.org\/10.1016\/j.ajpath.2022.09.003","DOI":"10.1016\/j.ajpath.2022.09.003"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"9.\tVainshtein A, Sandri M. Signaling Pathways That Control Muscle Mass. Int J Mol Sci 2020;21:4759. https:\/\/doi.org\/10.3390\/ijms21134759","DOI":"10.3390\/ijms21134759"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"10.\tBonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 2013;6:25-39. https:\/\/doi.org\/10.1242\/dmm.010389","DOI":"10.1242\/dmm.010389"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"11.\tYoshida T, Delafontaine P. Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells 2020;9:1970. https:\/\/doi.org\/10.3390\/cells9091970","DOI":"10.3390\/cells9091970"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"12.\tStitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, ET AL. The IGF-1\/PI3K\/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 2004;14:395-403. https:\/\/doi.org\/10.1016\/S1097-2765(04)00211-4","DOI":"10.1016\/s1097-2765(04)00211-4"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"13.\tBaar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, ET AL. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J 2002;16:1879-1886. https:\/\/doi.org\/10.1096\/fj.02-0367com","DOI":"10.1096\/fj.02-0367com"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"14.\tRussell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, ET AL. 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. Diabetes 2003;52:2874-2881. https:\/\/doi.org\/10.2337\/diabetes.52.12.2874","DOI":"10.2337\/diabetes.52.12.2874"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"15.\tBrault JJ, Jespersen JG, Goldberg AL. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J Biol Chem 2010;285:19460-19471. https:\/\/doi.org\/10.1074\/jbc.M110.113092","DOI":"10.1074\/jbc.m110.113092"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"16.\tAllen DL, Bandstra ER, Harrison BC, Thorng S, Stodieck LS, Kostenuik PJ, Morony S, ET AL. Effects of spaceflight on murine skeletal muscle gene expression. J Appl Physiol (1985) 2009;106:582-595. https:\/\/doi.org\/10.1152\/japplphysiol.90780.2008","DOI":"10.1152\/japplphysiol.90780.2008"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"17.\tCannavino J, Brocca L, Sandri M, Bottinelli R, Pellegrino MA. PGC1-\u03b1 over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice. J Physiol 2014;592:4575-4589. https:\/\/doi.org\/10.1113\/jphysiol.2014.275545","DOI":"10.1113\/jphysiol.2014.275545"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"18.\tKang C, Ji LL. PGC-1\u03b1 overexpression via local transfection attenuates mitophagy pathway in muscle disuse atrophy. Free Radic Biol Med 2016;93:32-40. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2015.12.032","DOI":"10.1016\/j.freeradbiomed.2015.12.032"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"19.\tSandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, ET AL. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 2006;103:16260-16265. https:\/\/doi.org\/10.1073\/pnas.0607795103","DOI":"10.1073\/pnas.0607795103"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"20.\tQin W, Pan J, Wu Y, Bauman W, Cardozo C. Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1a. Biochem Biophys Res Commun 2010;403:473-478. https:\/\/doi.org\/10.1016\/j.bbrc.2010.11.061","DOI":"10.1016\/j.bbrc.2010.11.061"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"21.\tBooth FW, Gollnick PD. Effects of disuse on the structure and function of skeletal muscle. Med Sci Sports Exerc 1983;15:415-420. https:\/\/doi.org\/10.1249\/00005768-198315050-00013","DOI":"10.1249\/00005768-198315050-00013"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"22.\tMirzoev TM. Skeletal Muscle Recovery from Disuse Atrophy: Protein Turnover Signaling and Strategies for Accelerating Muscle Regrowth. Int J Mol Sci 2020;21:7940. https:\/\/doi.org\/10.3390\/ijms21217940","DOI":"10.3390\/ijms21217940"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"23.\tJones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev 2016;10:CD009419. https:\/\/doi.org\/10.1002\/14651858.CD009419.pub3","DOI":"10.1002\/14651858.cd009419"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"24.\tMaffiuletti NA, Green DA, Vaz MA, Dirks ML. Neuromuscular Electrical Stimulation as a Potential Countermeasure for Skeletal Muscle Atrophy and Weakness During Human Spaceflight. Front Physiol 2019;10:1031. https:\/\/doi.org\/10.3389\/fphys.2019.01031","DOI":"10.3389\/fphys.2019.01031"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"25.\tNader GA, Esser KA. Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. J Appl Physiol (1985) 2001;90:1936-1942. https:\/\/doi.org\/10.1152\/jappl.2001.90.5.1936","DOI":"10.1152\/jappl.2001.90.5.1936"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"26.\tDow DE, Faulkner JA, Dennis RG. Distribution of rest periods between electrically generated contractions in denervated muscles of rats. Artif Organs 2005;29;432-435. https:\/\/doi.org\/10.1111\/j.1525-1594.2005.29086.x","DOI":"10.1111\/j.1525-1594.2005.29086.x"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"27.\tDoucet BM, Lam A, Griffin L. Neuromuscular electrical stimulation for skeletal muscle function. Yale J Biol Med 2012;85:201-215. https:\/\/doi.org\/10.1016\/j.jelekin.2011.12.005","DOI":"10.1016\/j.jelekin.2011.12.005"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"28.\tSillen MJ, Franssen FM, Gosker HR, Wouters EF, Spruit MA. Metabolic and structural changes in lower-limb skeletal muscle following neuromuscular electrical stimulation: a systematic review. PLoS One 2013;8:e69391. https:\/\/doi.org\/10.1371\/journal.pone.0069391","DOI":"10.1371\/journal.pone.0069391"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"29.\tde Freitas GR, Santo CCDE, de Machado-Pereira NAMM, Bobinski F, Dos Santos ARS, Ilha J. Early Cyclical Neuromuscular Electrical Stimulation Improves Strength and Trophism by Akt Pathway Signaling in Partially Paralyzed Biceps Muscle After Spinal Cord Injury in Rats. Phys Ther 2018;98:172-181. https:\/\/doi.org\/10.1093\/ptj\/pzx116","DOI":"10.1093\/ptj\/pzx116"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"30.\tRusso TL, Peviani SM, Durigan JL, Gigo-Benato D, Delfino GB, Salvini TF. Stretching and electrical stimulation reduce the accumulation of MyoD, myostatin and atrogin-1 in denervated rat skeletal muscle. J Muscle Res Cell Motil 2010;31:45-57. https:\/\/doi.org\/10.1007\/s10974-010-9203-z","DOI":"10.1007\/s10974-010-9203-z"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"31.\tDupont E, Cieniewski-Bernard C, Bastide B, Stevens L. Electrostimulation during hindlimb unloading modulates PI3K-AKT downstream targets without preventing soleus atrophy and restores slow phenotype through ERK. Am J Physiol Regul Integr Comp Physiol 2011;300:R408-R417. https:\/\/doi.org\/10.1152\/ajpregu.00793.2009","DOI":"10.1152\/ajpregu.00793.2009"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"32.\tDirks ML, Wall BT, Snijders T, Ottenbros CL, Verdijk LB, van Loon LJ. Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans. Acta Physiol (Oxf) 2014;210:628-641. https:\/\/doi.org\/10.1111\/apha.12200","DOI":"10.1111\/apha.12200"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"33.\tOga S, Goto K, Sakamoto J, Honda Y, Sasaki R, Ishikawa K, Kataoka H, ET AL. Mechanisms underlying immobilization-induced muscle pain in rats. Muscle Nerve 2020;61:662-670. https:\/\/doi.org\/10.1002\/mus.26840","DOI":"10.1002\/mus.26840"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"34.\tHonda Y, Tanaka N, Kajiwara Y, Kondo Y, Kataoka H, Sakamoto J, Akimoto R, ET AL. Effect of belt electrode-skeletal muscle electrical stimulation on immobilization-induced muscle fibrosis. PLoS One 2021;16:e0244120. https:\/\/doi.org\/10.1371\/journal.pone.0244120","DOI":"10.1101\/2020.12.04.411355"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"35.\tHintz CS, Coyle EF, Kaiser KK, Chi MM, Lowry OH. Comparison of muscle fiber typing by quantitative enzyme assays and by myosin ATPase staining. J Histochem Cytochem 1984;32:655-660. https:\/\/doi.org\/10.1177\/32.6.6202737","DOI":"10.1177\/32.6.6202737"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"36.\tOhira Y, Yoshinaga T, Nomura T, Kawano F, Ishihara A, Nonaka I, Roy RR, ET AL. Gravitational unloading effects on muscle fiber size, phenotype and myonuclear number. Adv Space Res 2002;30:777-781. https:\/\/doi.org\/10.1016\/S0273-1177(02)00395-2","DOI":"10.1016\/s0273-1177(02)00395-2"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"37.\tZhong H, Roy RR, Siengthai B, Edgerton VR. Effects of inactivity on fiber size and myonuclear number in rat soleus muscle. J Appl Physiol (1985) 2005;99:1494-1499. https:\/\/doi.org\/10.1152\/japplphysiol.00394.2005","DOI":"10.1152\/japplphysiol.00394.2005"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"38.\tWang J, Wang F, Zhang P, Liu H, He J, Zhang C, Fan M, ET AL. PGC-1\u03b1 over-expression suppresses the skeletal muscle atrophy and myofiber-type composition during hindlimb unloading. Biosci Biotechnol Biochem 2017;81:500-513. https:\/\/doi.org\/10.1080\/09168451.2016.1254531","DOI":"10.1080\/09168451.2016.1254531"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"39.\tCanon F, Goubel F, Guezennec CY. Effects of chronic low frequency stimulation on contractile and elastic properties of hindlimb suspended rat soleus muscle. Eur J Appl Physiol Occup Physiol 1998;77:118-124. https:\/\/doi.org\/10.1007\/s004210050309","DOI":"10.1007\/s004210050309"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"40.\tBoonyarom O, Kozuka N, Matsuyama K, Murakami S. Effect of electrical stimulation to prevent muscle atrophy on morphologic and histologic properties of hindlimb suspended rat hindlimb muscles. Am J Phys Med Rehabil 2009;88:719-726. https:\/\/doi.org\/10.1097\/PHM.0b013e31818e02d6","DOI":"10.1097\/phm.0b013e31818e02d6"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"41.\tDow DE, Cederna PS, Hassett CA, Kostrominova TY, Faulkner JA, Dennis RG. Number of contractions to maintain mass and force of a denervated rat muscle. Muscle Nerve 2004;30:77-86. https:\/\/doi.org\/10.1002\/mus.20054","DOI":"10.1002\/mus.20054"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"42.\tValero-Breton M, Warnier G, Castro-Sepulveda M, Deldicque L, Zbinden-Foncea H. Acute and Chronic Effects of High Frequency Electric Pulse Stimulation on the Akt\/mTOR Pathway in Human Primary Myotubes. Front Bioeng Biotechnol 2020;8:565679. https:\/\/doi.org\/10.3389\/fbioe.2020.565679","DOI":"10.3389\/fbioe.2020.565679"}],"container-title":["Physiological Research"],"original-title":[],"language":"en","deposited":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T10:07:33Z","timestamp":1710151653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2024\/73_105.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,6]]},"references-count":42,"journal-issue":{"issue":"1\/2024","published-online":{"date-parts":[[2024,3,6]]}},"URL":"https:\/\/doi.org\/10.33549\/physiolres.935157","relation":{},"ISSN":["1802-9973","0862-8408"],"issn-type":[{"value":"1802-9973","type":"electronic"},{"value":"0862-8408","type":"print"}],"subject":[],"published":{"date-parts":[[2024,3,6]]}}}