{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:12:33Z","timestamp":1787836353899,"version":"build-2784847793"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T00:00:00Z","timestamp":1620000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease characterized by progressive muscle weakness and wasting. Stimulation of AMP-activated protein kinase (AMPK) has been demonstrated to increase muscle function and protect muscle against damage in dystrophic mice. Metformin is a widely used anti-hyperglycemic drug and has been shown to be an indirect activator of AMPK. Based on these findings, we sought to determine the effects of metformin on neuromuscular deficits in mdx murine model of DMD. In this study, we found metformin treatment increased muscle strength accompanied by elevated twitch and tetanic force of tibialis anterior (TA) muscle in mdx mice. Immunofluorescence and electron microscopy analysis of metformin-treated mdx muscles revealed an improvement in muscle fiber membrane integrity. Electrophysiological studies showed the amplitude of miniature endplate potentials (mEPP) was increased in treated mice, indicating metformin also improved neuromuscular transmission of the mdx mice. Analysis of mRNA and protein levels from muscles of treated mice showed an upregulation of AMPK phosphorylation and dystrophin-glycoprotein complex protein expression. In conclusion, metformin can indeed improve muscle function and diminish neuromuscular deficits in mdx mice, suggesting its potential use as a therapeutic drug in DMD patients.<\/jats:p>","DOI":"10.3389\/fphys.2021.642908","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T05:15:22Z","timestamp":1620018922000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["Metformin Increases Sarcolemma Integrity and Ameliorates Neuromuscular Deficits in a Murine Model of Duchenne Muscular Dystrophy"],"prefix":"10.3389","volume":"12","author":[{"given":"Xia","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiankun","family":"Hui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suqi","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkang","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifeng","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinsheng","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"B1","first-page":"2387","article-title":"Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia\/reperfusion.","volume":"18","author":"Abd-Elsameea","year":"2014","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1083\/jcb.150.6.1385","article-title":"Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin.","volume":"150","author":"Adams","year":"2000","journal-title":"J. Cell Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1002\/stem.1402","article-title":"A new immuno-, dystrophin-deficient model, the NSG-mdx(4Cv) mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation.","volume":"31","author":"Arpke","year":"2013","journal-title":"Stem Cells"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: historical overview.","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"B5","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.mcn.2008.12.011","article-title":"Truncated dystrophins can influence neuromuscular synapse structure.","volume":"40","author":"Banks","year":"2009","journal-title":"Mol. Cell. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/s0029-7844(03)00045-0","article-title":"Metformin for the treatment of polycystic ovary syndrome.","volume":"101","author":"Barbieri","year":"2003","journal-title":"Obstetrics Gynecol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"9770","DOI":"10.1523\/JNEUROSCI.0174-16.2016","article-title":"Schwann cells in neuromuscular junction formation and maintenance.","volume":"36","author":"Barik","year":"2016","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"13892","DOI":"10.1523\/JNEUROSCI.1733-14.2014","article-title":"LRP4 is critical for neuromuscular junction maintenance.","volume":"34","author":"Barik","year":"2014","journal-title":"J. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"23451","DOI":"10.1074\/jbc.M111.331926","article-title":"Activation of AMP-activated protein kinase stimulates Na+,K+-ATPase activity in skeletal muscle cells.","volume":"287","author":"Benziane","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1073\/pnas.81.4.1189","article-title":"X chromosome-linked muscular dystrophy (mdx) in the mouse.","volume":"81","author":"Bulfield","year":"1984","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B11","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/s1474-4422(09)70271-6","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management.","volume":"9","author":"Bushby","year":"2010","journal-title":"Lancet Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.cell.2013.02.035","article-title":"Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism.","volume":"153","author":"Cabreiro","year":"2013","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/338259a0","article-title":"Association of dystrophin and an integral membrane glycoprotein.","volume":"338","author":"Campbell","year":"1989","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1111\/j.1365-2990.1988.tb00866.x","article-title":"The mdx mouse skeletal muscle myopathy: I. A histological, morphometric and biochemical investigation.","volume":"14","author":"Coulton","year":"1988","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nrm2024","article-title":"Molecular mechanisms of muscular dystrophies: old and new players.","volume":"7","author":"Davies","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.tem.2018.02.010","article-title":"The role of AMPK in neuromuscular biology and disease.","volume":"29","author":"Dial","year":"","journal-title":"Trends Endocrinol. Metab."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2950","DOI":"10.1096\/fj.201700868RRR","article-title":"The role of AMP-activated protein kinase in the expression of the dystrophin-associated protein complex in skeletal muscle.","volume":"32","author":"Dial","year":"","journal-title":"FASEB J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/0960-8966(91)90039-u","article-title":"Population frequencies of inherited neuromuscular diseases\u2013a world survey.","volume":"1","author":"Emery","year":"1991","journal-title":"Neuromuscul. Disord."},{"key":"B19","doi-asserted-by":"publisher","first-page":"13663","DOI":"10.1073\/pnas.1512991112","article-title":"Dystrophin-glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling.","volume":"112","author":"Garbincius","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147634","article-title":"Improved muscle function in duchenne muscular dystrophy through L-Arginine and metformin: an investigator-initiated, open-label, single-center, proof-of-concept-study.","volume":"11","author":"Hafner","year":"2016","journal-title":"PLoS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.14171","article-title":"Effect of Combination l-citrulline and metformin treatment on motor function in patients with duchenne muscular dystrophy: a randomized clinical trial.","volume":"2","author":"Hafner","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"B22","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1046\/j.0021-8782.2001.00008.x","article-title":"Evans Blue Dye as an in vivo marker of myofibre damage: optimising parameters for detecting initial myofibre membrane permeability.","author":"Hamer","year":"2002","journal-title":"J. Anat."},{"key":"B23","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/s0955-0674(99)00024-1","article-title":"Dystroglycan inside and out.","volume":"11","author":"Henry","year":"1999","journal-title":"Curr. Opin. Cell Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/0092-8674(87)90579-4","article-title":"Dystrophin: the protein product of the Duchenne muscular dystrophy locus.","volume":"51","author":"Hoffman","year":"","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1126\/science.3659917","article-title":"Conservation of the Duchenne muscular dystrophy gene in mice and humans.","volume":"238","author":"Hoffman","year":"","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/s0014-5793(00)01195-9","article-title":"Biosynthesis of dystroglycan: processing of a precursor propeptide.","volume":"468","author":"Holt","year":"2000","journal-title":"FEBS Lett."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.2337\/dc12-0719","article-title":"Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease.","volume":"36","author":"Hong","year":"2013","journal-title":"Diabetes Care"},{"key":"B28","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/355696a0","article-title":"Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix.","volume":"355","author":"Ibraghimov-Beskrovnaya","year":"1992","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1152\/japplphysiol.00084","article-title":"Dihydropyridine and ryanodine receptor binding after eccentric contractions in mouse skeletal muscle.","volume":"96","author":"Ingalls","year":"1985","journal-title":"J. Appl. Physiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1007\/s00125-012-2534-0","article-title":"Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).","volume":"55","author":"Inzucchi","year":"2012","journal-title":"Diabetologia"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-2-16","article-title":"Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model.","volume":"2","author":"Jahnke","year":"2012","journal-title":"Skeletal Muscle"},{"key":"B32","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1113\/jphysiol.2006.109942","article-title":"Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise.","volume":"574","author":"J\u00f8rgensen","year":"2006","journal-title":"J. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1096\/fj.201700442R","article-title":"AMPK in skeletal muscle function and metabolism.","volume":"32","author":"Kj\u00f8bsted","year":"2018","journal-title":"FASEB J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/s0006-8993(99)01737-0","article-title":"Dystrophin is required for organizing large acetylcholine receptor aggregates.","volume":"28","author":"Kong","year":"1999","journal-title":"Brain Res."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114018","article-title":"Metformin protects skeletal muscle from cardiotoxin induced degeneration.","volume":"9","author":"Langone","year":"2014","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1161\/01.RES.0000126574.61061.25","article-title":"The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma.","volume":"94","author":"Lapidos","year":"2004","journal-title":"Circ. Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.molmed.2013.07.002","article-title":"AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy.","volume":"19","author":"Ljubicic","year":"2013","journal-title":"Trends Mol. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1002\/mus.24692","article-title":"Metformin increases peroxisome proliferator-activated receptor gamma Co-activator-1alpha and utrophin a expression in dystrophic skeletal muscle.","volume":"52","author":"Ljubicic","year":"2015","journal-title":"Muscle Nerve"},{"key":"B39","doi-asserted-by":"publisher","first-page":"C110","DOI":"10.1152\/ajpcell.00183.2011","article-title":"Chronic AMPK stimulation attenuates adaptive signaling in dystrophic skeletal muscle.","volume":"302","author":"Ljubicic","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3478","DOI":"10.1093\/hmg\/ddr265","article-title":"Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle.","volume":"20","author":"Ljubicic","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"B41","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1007\/978-981-10-3292-9_13","article-title":"Therapeutic potential of skeletal muscle plasticity and slow muscle programming for muscular dystrophy and related muscle conditions","author":"Lynch","year":"2017","journal-title":"The Plasticity of Skeletal Muscle"},{"key":"B42","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.bcp.2018.04.022","article-title":"Effect of a long-term treatment with metformin in dystrophic mdx mice: a reconsideration of its potential clinical interest in Duchenne muscular dystrophy.","volume":"154","author":"Mantuano","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1016\/s0960-9822(00)00742-9","article-title":"Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.","volume":"10","author":"Marsin","year":"2000","journal-title":"Curr. Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/0022-510x(93)90130-q","article-title":"Age-related changes in replication of myogenic cells in mdx mice: quantitative autoradiographic studies.","volume":"119","author":"McGeachie","year":"1993","journal-title":"J. Neurol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"15457","DOI":"10.1074\/jbc.R200031200","article-title":"Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function.","volume":"278","author":"Michele","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B46","doi-asserted-by":"crossref","first-page":"31629","DOI":"10.1074\/jbc.M212831200","article-title":"Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells.","volume":"278","author":"Morrow","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.cmet.2013.06.017","article-title":"AMPK\u03b11 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration.","volume":"18","author":"Mounier","year":"2013","journal-title":"Cell Metab."},{"key":"B48","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.tem.2015.02.009","article-title":"Expanding roles for AMPK in skeletal muscle plasticity.","volume":"26","author":"Mounier","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"B49","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/s1474-4422(03)00585-4","article-title":"Dystrophin and mutations: one gene, several proteins, multiple phenotypes.","volume":"2","author":"Muntoni","year":"2003","journal-title":"Lancet Neurol."},{"key":"B50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mrgentox.2006.06.036","article-title":"Metformin does not prevent DNA damage in lymphocytes despite its antioxidant properties against cumene hydroperoxide-induced oxidative stress.","volume":"611","author":"Onaran","year":"2006","journal-title":"Mutat Res."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5425","article-title":"Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy.","volume":"5","author":"Pal","year":"2014","journal-title":"Nat. Commun."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.stemcr.2015.04.007","article-title":"Fibrogenic cell plasticity blunts tissue regeneration and aggravates muscular dystrophy.","volume":"4","author":"Pessina","year":"2015","journal-title":"Stem Cell Rep."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2781","DOI":"10.1093\/hmg\/ddx173","article-title":"Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway.","volume":"26","author":"Petrillo","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2015.00252","article-title":"Pre- and postsynaptic changes in the neuromuscular junction in dystrophic mice.","volume":"6","author":"Pratt","year":"2015","journal-title":"Front. Physiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1002\/cphy.c140048","article-title":"The Dystrophin complex: structure, function, and implications for therapy.","volume":"5","author":"Quan","year":"2015","journal-title":"Compr. Physiol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1042\/bj3350533","article-title":"AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release.","volume":"335","author":"Salt","year":"1998","journal-title":"Biochem. J."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2568","DOI":"10.1161\/CIRCULATIONAHA.108.798561","article-title":"Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase.","volume":"119","author":"Sasaki","year":"2009","journal-title":"Circulation"},{"key":"B58","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1212\/WNL.35.9.1396","article-title":"Muscle mitochondria from patients with Duchenne muscular dystrophy have a normal beta oxidation, but an impaired oxidative phosphorylation.","volume":"35","author":"Scholte","year":"1985","journal-title":"Neurology"},{"key":"B59","doi-asserted-by":"publisher","first-page":"5190","DOI":"10.1172\/JCI66039","article-title":"Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis.","volume":"123","author":"Shen","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3390\/nu9050524","article-title":"Retrospective evaluation of metformin and\/or metformin plus a new polysaccharide complex in treating severe hyperinsulinism and insulin resistance in obese children and adolescents with metabolic syndrome.","volume":"9","author":"Stagi","year":"2017","journal-title":"Nutrients"},{"key":"B61","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1096\/fj.13-238972","article-title":"Muscle-specific AMPK \u03b21\u03b22-null mice display a myopathy due to loss of capillary density in nonpostural muscles.","volume":"28","author":"Thomas","year":"2014","journal-title":"FASEB J."},{"key":"B62","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1093\/brain\/110.2.269","article-title":"The mutant mdx: inherited myopathy in the mouse. Morphological studies of nerves, muscles and end-plates.","author":"Torres","year":"1987","journal-title":"Brain"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01236","article-title":"Metformin and autoimmunity: a \u201cnew deal\u201d of an old drug.","volume":"9","author":"Ursini","year":"2018","journal-title":"Front. Immunol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: an overview.","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin. Sci. (Lond)"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015354","article-title":"Skeletal muscle NADPH oxidase is increased and triggers stretch-induced damage in the mdx mouse.","volume":"5","author":"Whitehead","year":"2010","journal-title":"PLoS One"},{"key":"B66","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1093\/hmg\/6.6.831","article-title":"Dystroglycan is essential for early embryonic development: disruption of Reichert\u2019s membrane in Dag1-null mice.","volume":"6","author":"Williamson","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"B67","doi-asserted-by":"publisher","first-page":"E299","DOI":"10.1152\/ajpendo.1996.270.2.E299","article-title":"Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise.","volume":"270","author":"Winder","year":"1996","journal-title":"Am. J. Physiol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"5935","DOI":"10.1523\/JNEUROSCI.2904-18.2019","article-title":"Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids.","volume":"39","author":"Zemdegs","year":"2019","journal-title":"J. Neurosci."},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/8768327","article-title":"Metformin protects against oxidative stress injury induced by ischemia\/reperfusion via regulation of the lncRNA-H19\/miR-148a-3p\/Rock2 Axis.","volume":"2019","author":"Zeng","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"B70","doi-asserted-by":"publisher","first-page":"3465","DOI":"10.1523\/JNEUROSCI.2934-16.2017","article-title":"Muscle yap is a regulator of neuromuscular junction formation and regeneration.","volume":"37","author":"Zhao","year":"2017","journal-title":"J. Neurosci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1172\/jci13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action.","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Invest."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.642908\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T05:15:27Z","timestamp":1620018927000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.642908\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,3]]},"references-count":71,"alternative-id":["10.3389\/fphys.2021.642908"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.642908","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,3]]},"article-number":"642908"}}