<?xml version="1.1" encoding="utf-8"?>
<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">PAR</journal-id><journal-title-group><journal-title>Proceedings of Anticancer Research</journal-title></journal-title-group><issn>2208-3545</issn><eissn>2208-3553</eissn><publisher><publisher-name>Bio-Byword Scientific Publishing Pty. Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.26689/par.v7i6.5570</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title>Effects of Neuromuscular Electrical Stimulation in Combination with Glutamine Administration on Skeletal Muscle Atrophy in Colon-26 Tumor-Bearing Mice</title><url>https://artdesignp.com/journal/PAR/7/6/10.26689/par.v7i6.5570</url><author>TatebayashiDaisuke,HimoriKoichi,AshidaYuki,YamadaTakashi</author><pub-date pub-type="publication-year"><year>2023</year></pub-date><volume>7</volume><issue>6</issue><history><date date-type="pub"><published-time>2023-11-22</published-time></date></history><abstract>The depressed protein synthetic response, a phenomenon termed anabolic resistance, has been shown to be involved in muscle wasting induced by cancer cachexia. Moreover, a positive relationship between the protein synthetic rate and intracellular glutamine (GLN) concentration has been found in skeletal muscles. This study investigated the effects of neuromuscular electrical stimulation (ES) and GLN administration on muscle wasting and GLN metabolism in colon-26 (C-26) tumor-bearing mice. CD2F1 mice were divided into 8 groups: control (CNT), CNT+ES, CNT+GLN, CNT+ES+GLN, C-26, C-26+ES, C-26+GLN, C-26+ES+GLN. Cancer cachexia was induced by subcutaneous injection of C-26 cells and developed for four weeks. ES was performed on the left plantar flexor muscles every other day, and GLN (1 g/kg) was administered daily intraperitoneally starting one day after the C-26 injection. Tumor-free body mass and fast-twitch gastrocnemius (Gas) muscle weight were lower in the C-26 group than in the CNT group (-19% and -17%, respectively). Neither ES training nor GLN administration, alone or in combination, ameliorated the loss of Gas muscle weight in the C-26 mice. However, ES training in combination with GLN administration inhibited the increased expression of GLN synthetase (GS) in the C-26 muscles. Thus, it is likely that GLN plays a critical role in muscle protein metabolism and, therefore, can be targeted as a tentative treatment of cancer cachexia.</abstract><keywords/></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>Tisdale MJ, 2002, Cachexia in Cancer Patients. Nat Rev Cancer, 2(11): 862–871. https://doi.org/10.1038/nrc927</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B2" content-type="article"><label>2</label><element-citation publication-type="journal"><p>Brennan MF, 1977, Uncomplicated Starvation Versus Cancer Cachexia. Cancer Res, 37(7 Pt 2): 2359–2364.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B3" content-type="article"><label>3</label><element-citation publication-type="journal"><p>Evans WK, Makuch R, Clamon GH, et al., 1985, Limited Impact of Total Parenteral Nutrition on Nutritional Status During Treatment for Small Cell Lung Cancer. Cancer Res, 45(7): 3347–3353.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B4" content-type="article"><label>4</label><element-citation publication-type="journal"><p>DeWys WD, 1980, Nutritional Care of the Cancer Patient. JAMA, 244(4): 374–376. https://doi.org/10.1001/jama.1980.03310040056033</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B5" content-type="article"><label>5</label><element-citation publication-type="journal"><p>Sugiyama K, Narita Y, Mitani S, et al., 2018, Baseline Sarcopenia and Skeletal Muscle Loss During Chemotherapy Affect Survival Outcomes in Metastatic Gastric Cancer. Anticancer Res, 38(10): 5859–5866. https://doi.org/10.21873/anticanres.12928</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B6" content-type="article"><label>6</label><element-citation publication-type="journal"><p>Zhou X, Wang JL, Lu J, et al., 2010, Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival. Cell, 142(4): 531–543. https://doi.org/10.1016/j.cell.2010.07.011</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B7" content-type="article"><label>7</label><element-citation publication-type="journal"><p>Hardee JP, Montalvo RN, Carson JA, 2017, Linking Cancer Cachexia-Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism. Oxid Med Cell Longev, 2017: 8018197. https://doi.org/10.1155/2017/8018197</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B8" content-type="article"><label>8</label><element-citation publication-type="journal"><p>Phillips SM, Glover EI, Rennie MJ, 2009, Alterations of Protein Turnover Underlying Disuse Atrophy in Human Skeletal Muscle. J Appl Physiol (1985), 107(3): 645–654. https://doi.org/10.1152/japplphysiol.00452.2009</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B9" content-type="article"><label>9</label><element-citation publication-type="journal"><p>Shad BJ, Thompson JL, Breen L, 2016, Does the Muscle Protein Synthetic Response to Exercise and Amino Acid-Based Nutrition Diminish with Advancing Age? A Systematic Review. Am J Physiol Endocrinol Metab, 311(5): E803–E817. https://doi.org/10.1152/ajpendo.00213.2016</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B10" content-type="article"><label>10</label><element-citation publication-type="journal"><p>White JP, Puppa MJ, Gao S, et al., 2013, Muscle mTORC1 Suppression by IL-6 During Cancer Cachexia: A Role for AMPK. Am J Physiol Endocrinol Metab, 304(10): E1042–E1052. https://doi.org/10.1152/ajpendo.00410.2012</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B11" content-type="article"><label>11</label><element-citation publication-type="journal"><p>Rennie MJ, MacLennan PA, Hundal HS, et al., 1989, Skeletal Muscle Glutamine Transport, Intramuscular Glutamine Concentration, and Muscle-Protein Turnover. Metabolism, 38(8 Suppl 1): 47–51. https://doi.org/10.1016/0026-0495(89)90140-6</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B12" content-type="article"><label>12</label><element-citation publication-type="journal"><p>Askanazi J, Furst P, Michelsen CB, et al., 1980, Muscle and Plasma Amino Acids after Injury: Hypocaloric Glucose vs. Amino Acid Infusion. Ann Surg, 191(4): 465–472. https://doi.org/10.1097/00000658-198004000-00013</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B13" content-type="article"><label>13</label><element-citation publication-type="journal"><p>MacLennan PA, Brown RA, Rennie MJ, 1987, A Positive Relationship Between Protein Synthetic Rate and IntracellularGlutamine Concentration in Perfused Rat Skeletal Muscle. FEBS Lett, 215(1): 187–191. https://doi.org/10.1016/0014-5793(87)80139-4</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B14" content-type="article"><label>14</label><element-citation publication-type="journal"><p>Chen MK, Espat NJ, Bland KI, et al., 1993, Influence of Progressive Tumor Growth on Glutamine Metabolism in Skeletal Muscle and Kidney. Ann Surg, 217(6): 655–666; discussion 666-7. https://doi.org/10.1097/00000658-199306000-00007</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B15" content-type="article"><label>15</label><element-citation publication-type="journal"><p>Parry-Billings M, Leighton B, Dimitriadis GD, et al., 1991, The Effect of Tumour Bearing on Skeletal Muscle Glutamine Metabolism. Int J Biochem, 23(9): 933–937. https://doi.org/10.1016/0020-711x(91)90082-x</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B16" content-type="article"><label>16</label><element-citation publication-type="journal"><p>Austgen TR, Dudrick PS, Sitren H, et al., 1992, The Effects of Glutamine-Enriched Total Parenteral Nutrition of Tumor Growth and Host Tissues. Ann Surg, 215(2): 107–113. https://doi.org/10.1097/00000658-199202000-00003</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B17" content-type="article"><label>17</label><element-citation publication-type="journal"><p>Klimberg VS, Souba WW, Salloum RM, et al., 1990, Glutamine-Enriched Diets Support Muscle Glutamine Metabolism Without Stimulating Tumor Growth. J Surg Res, 48(4): 319–323. https://doi.org/10.1016/0022-4804(90)90066-b</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B18" content-type="article"><label>18</label><element-citation publication-type="journal"><p>Kaihara A, 1994, Protein Metabolism in Tumor-Bearing Carriers: Effects of Glutamine Administration on Protein Metabolic Dynamics in Tumor-Bearing Carriers. Jap J Kurume Med Assoc, 57(2): 224–232.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B19" content-type="article"><label>19</label><element-citation publication-type="journal"><p>Damink SWO, de Blaauw I, Deutz NE, et al., 1999, Effects In Vivo of Decreased Plasma and Intracellular Muscle Glutamine Concentration on Whole-Body and Hindquarter Protein Kinetics in Rats. Clin Sci (Lond), 96(6): 639–646. https://doi.org/10.1042/cs19980389</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B20" content-type="article"><label>20</label><element-citation publication-type="journal"><p>Tisdale MJ, 2009, Mechanisms of Cancer Cachexia. Physiol Rev, 89(2): 381–410. https://doi.org/10.1152/physrev.00016.2008</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B21" content-type="article"><label>21</label><element-citation publication-type="journal"><p>Maffiuletti NA, 2010, Physiological and Methodological Considerations for the Use of Neuromuscular Electrical Stimulation. Eur J Appl Physiol, 110(2): 223–234. https://doi.org/10.1007/s00421-010-1502-y</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B22" content-type="article"><label>22</label><element-citation publication-type="journal"><p>Gregory CM, Bickel CS, 2005, Recruitment Patterns in Human Skeletal Muscle During Electrical Stimulation. Phys Ther, 85(4): 358–364.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B23" content-type="article"><label>23</label><element-citation publication-type="journal"><p>Maddocks M, Gao W, Higginson IJ, et al., 2013, Neuromuscular Electrical Stimulation for Muscle Weakness in Adults with Advanced Disease. Cochrane Database Syst Rev, 1: CD009419. https://doi.org/10.1002/14651858.CD009419.pub2</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B24" content-type="article"><label>24</label><element-citation publication-type="journal"><p>al-Majid S, McCarthy DO, 2001, Resistance Exercise Training Attenuates Wasting of the Extensor Digitorum Longus Muscle in Mice Bearing the Colon-26 Adenocarcinoma. Biol Res Nurs, 2(3): 155–166. https://doi.org/10.1177/109980040100200301</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B25" content-type="article"><label>25</label><element-citation publication-type="journal"><p>Tatebayashi D, Hinomori K, Abe M, et al., 2016, Effects of Neuromuscular Electrical Stimulation Therapy on Muscle Mass Loss Associated with Cancer Cachexia. Jap Phys Ther Sci, 23: 35–43.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B26" content-type="article"><label>26</label><element-citation publication-type="journal"><p>Murphy KT, Chee A, Trieu J, et al., 2012, Importance of Functional and Metabolic Impairments in the Characterization of the C-26 Murine Model of Cancer Cachexia. Dis Model Mech, 5(4): 533–545. https://doi.org/10.1242/dmm.008839</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B27" content-type="article"><label>27</label><element-citation publication-type="journal"><p>Meador BM, Huey KA, 2009, Glutamine Preserves Skeletal Muscle Force During an Inflammatory Insult. Muscle Nerve, 40(6): 1000–1007. https://doi.org/10.1002/mus.21430</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B28" content-type="article"><label>28</label><element-citation publication-type="journal"><p>Gondin J, Giannesini B, Vilmen C, et al., 2010, Effects of Stimulation Frequency and Pulse Duration on Fatigue and Metabolic Cost During a Single Bout of Neuromuscular Electrical Stimulation. Muscle Nerve, 41(5): 667–678. https://doi.org/10.1002/mus.21572</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B29" content-type="article"><label>29</label><element-citation publication-type="journal"><p>Shimada H, Hamakawa M, Ishida A, et al., 2013, Low-Speed Treadmill Running Exercise Improves Memory Function after Transient Middle Cerebral Artery Occlusion in Rats. Behav Brain Res, 243: 21–27. https://doi.org/ 10.1016/j.bbr.2012.12.018</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B30" content-type="article"><label>30</label><element-citation publication-type="journal"><p>Bradford MM, 1976, A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Anal Biochem, 72: 248–254. https://doi.org/10.1006/abio.1976.9999</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B31" content-type="article"><label>31</label><element-citation publication-type="journal"><p>Fearon K, Strasser F, Anker SD, et al., 2011, Definition and Classification of Cancer Cachexia: An International Consensus. Lancet Oncol, 12(5): 489–495. https://doi.org/10.1016/S1470-2045(10)70218-7</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B32" content-type="article"><label>32</label><element-citation publication-type="journal"><p>Aulino P, Berardi E, Cardillo VM, et al., 2010, Molecular, Cellular and Physiological Characterization of the Cancer Cachexia-Inducing C26 Colon Carcinoma in Mouse. BMC Cancer, 10: 363. https://doi.org/10.1186/1471-2407-10-363</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B33" content-type="article"><label>33</label><element-citation publication-type="journal"><p>Falduto MT, Young AP, Hickson RC, 1992, Exercise Interrupts Ongoing Glucocorticoid-Induced Muscle Atrophy and Glutamine Synthetase Induction. Am J Physiol, 263(3): E1157–E1163. https://doi.org/10.1152/ajpendo.2006.263.6.E1157</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B34" content-type="article"><label>34</label><element-citation publication-type="journal"><p>Watford M, Wu G, 2005, Glutamine Metabolism in Uricotelic Species: Variation in Skeletal Muscle Glutamine Synthetase, Glutaminase, Glutamine Levels and Rates of Protein Synthesis. Comp Biochem Physiol B Biochem Mol Bio, 149(4): 607–614. https://doi.org/10.1016/j.cbpc.2004.12.009</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B35" content-type="article"><label>35</label><element-citation publication-type="journal"><p>Hickson RC, Wegrzyn LE, Osborne DF, et al., 1996, Glutamine Interferes with Glucocorticoid-Induced Expression of Glutamine Synthetase in Skeletal Muscle. Am J Physiol, 270(5 Pt 1): E912–E917. https://doi.org/10.1152/ajpendo.1996.270.5.E912</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B36" content-type="article"><label>36</label><element-citation publication-type="journal"><p>Lambertucci AC, Lambertucci RH, Hirabara SM, et al., 2012, Glutamine Supplementation Stimulates Protein-Synthetic and Inhibits Protein-Degradative Signaling Pathways in Skeletal Muscle of Diabetic Rats. PLoS ONE, 8(6): e50390. https://doi.org/10.1371/journal.pone.0050390</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B37" content-type="article"><label>37</label><element-citation publication-type="journal"><p>Salomão EM, Gomes-Marcondes MC, 2012, Light Aerobic Physical Exercise in Combination with Leucine and/or Glutamine-Rich Diet Can Improve the Body Composition and Muscle Protein Metabolism in Young Tumor-Bearing Rats. J Physiol Biochem, 68(4): 493–501. https://doi.org/10.1007/s13105-012-0164-0</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B38" content-type="article"><label>38</label><element-citation publication-type="journal"><p>Hardee JP, Mangum JE, Gao S, et al., 2016, Eccentric Contraction-Induced Myofiber Growth in Tumor-Bearing Mice. J Appl Physiol (1985), 120(1): 29–37. https://doi.org/10.1152/japplphysiol.00416.2015</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B39" content-type="article"><label>39</label><element-citation publication-type="journal"><p>Tatebayashi D, Himori K, Yamada R, et al., 2018, High-Intensity Eccentric Training Ameliorates Muscle Wasting in Colon 26 Tumor-Bearing Mice. PloS ONE, 13(6): e0199050. https://doi.org/10.1371/journal.pone.0199050</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B40" content-type="article"><label>40</label><element-citation publication-type="journal"><p>Ashida Y, Himori K, Tatebayashi D, et al., 2018, Effects of Contraction Mode and Stimulation Frequency on Electrical Stimulation-Induced Skeletal Muscle Hypertrophy. J Appl Physiol (1985), 124(2): 341–348. https://doi.org/10.1152/japplphysiol.00708.2017</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B41" content-type="article"><label>41</label><element-citation publication-type="journal"><p>Banduseela V, Ochala J, Lamberg K, et al., 2007, Muscle Paralysis and Myosin Loss in a Patient with Cancer Cachexia. Acta Myol, 26(3): 136–144.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B42" content-type="article"><label>42</label><element-citation publication-type="journal"><p>Acharyya W, Butchbach MER, Sahenk Z, et al., 2005, Dystrophin Glycoprotein Complex Dysfunction: A Regulatory Link Between Muscular Dystrophy and Cancer Cachexia. Cancer Cell, 8(5): 421–432. https://doi.org/10.1016/j.ccr.2005.10.004</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B43" content-type="article"><label>43</label><element-citation publication-type="journal"><p>Cosper PF, Leinwand LA, 2012, Myosin Heavy Chain is not Selectively Decreased in Murine Cancer Cachexia. Int J Cancer, 130(11): 2722–2727. https://doi.org/10.1002/ijc.26298</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B44" content-type="article"><label>44</label><element-citation publication-type="journal"><p>Mozaffar T, Haddad F, Zeng M, et al., 2007, Molecular and Cellular Defects of Skeletal Muscle in an Animal Model of Acute Quadriplegic Myopathy. Muscle Nerve, 35(1): 55–65. https://doi.org/10.1002/mus.20647</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B45" content-type="article"><label>45</label><element-citation publication-type="journal"><p>Tanaka Y, Eda H, Tanaka T, et al., 1990, Experimental Cancer Cachexia Induced by Transplantable Colon 26 Adenocarcinoma in Mice. Cancer Res, 50(8): 2290–2295.</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B46" content-type="article"><label>46</label><element-citation publication-type="journal"><p>Jepson MM, Bates PC, Broadbent P, et al., 1988, Relationship between Glutamine Concentration and Protein Synthesis in Rat Skeletal Muscle. Am J Physiol, 255(2 Pt 1): E166–E172. https://doi.org/10.1152/ajpendo.1988.255.2.E166</p><pub-id pub-id-type="doi"/></element-citation></ref><ref id="B47" content-type="article"><label>47</label><element-citation publication-type="journal"><p>Biolo G, Iscra F, Bosutti A, et al., 2000, Growth Hormone Decreases Muscle Glutamine Production and Stimulates Protein Synthesis in Hypercatabolic Patients. Am J Physiol Endocrinol Metab, 279(2): E323–E332. https://doi.org/10.1152/ajpendo.2000.279.2.E323</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
