{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T17:10:48Z","timestamp":1781197848201,"version":"3.54.1"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS34100"],"award-info":[{"award-number":["NS34100"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings to minimize secondary brain injury. The efficacy of therapeutic hypothermia in chronic neurodegenerative disorders has not been examined. We tested the hypothesis that mild hypothermia\/cold acclimation is therapeutic in a transgenic mouse model of ALS caused by expression of mutated human superoxide dismutase-1 gene. At presymptomatic stages of disease, body temperatures (oral and axial) of mutant male mice were persistently hyperthermic (38\u201338.5 \u00b0C) compared to littermate controls, but at end-stage disease mice were generally hypothermic (36\u201336.5 \u00b0C). Presymptomatic mutant mice (awake-freely moving) were acclimated to systemic mild hypothermia using an environmentally controlled chamber (12 h-on\/12-off or 24 h-on\/24 h-off) to lower body temperature (1\u20133 \u00b0C). Cooled ALS mice showed a significant delay in disease onset (103\u2013112 days) compared to normothermia mice (80\u201390 days) and exhibited significant attenuation of functional decline in motor performance. Cooled mice examined at 80 days had reduced motor neuron loss, mitochondrial swelling, and spinal cord inflammation compared to non-cooled mice. Cooling attenuated the loss of heat-shock protein 70, mitochondrial uncoupling protein-3, and sumoylated-1 (SUMO1)-conjugated proteins in skeletal muscle and disengaged the mitochondrial permeability transition pore. Cooled ALS mice had a significant extension of lifespan (148 \u00b1 7 days) compared to normothermic mice (135 \u00b1 4 days). Thus, intermittent systemic mild hypothermia is therapeutic in mouse ALS with protective effects manifested within the CNS and skeletal muscle that target mitochondria.<\/jats:p>","DOI":"10.3390\/cells10020320","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T12:02:10Z","timestamp":1612440130000},"page":"320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS"],"prefix":"10.3390","volume":"10","author":[{"given":"Lee J.","family":"Martin","sequence":"first","affiliation":[{"name":"Departments of Pathology, Division of Neuropathology, Neuroscience, and Anesthesiology and Critical Medicine and the Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark V.","family":"Niedzwiecki","sequence":"additional","affiliation":[{"name":"Departments of Pathology, Division of Neuropathology, Neuroscience, and Anesthesiology and Critical Medicine and the Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Wong","sequence":"additional","affiliation":[{"name":"Departments of Pathology, Division of Neuropathology, Neuroscience, and Anesthesiology and Critical Medicine and the Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM200105313442207","article-title":"Amyotrophic lateral sclerosis","volume":"344","author":"Rowland","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fnagi.2017.00068","article-title":"ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?","volume":"9","author":"Petrov","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"839","DOI":"10.3390\/ph3040839","article-title":"Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases","volume":"3","author":"Martin","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1089\/ther.2019.0001","article-title":"A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis","volume":"9","author":"Jackson","year":"2019","journal-title":"Ther. Hypothermia Temp. Manag."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1007\/s00415-009-5100-z","article-title":"Hypermetabolism in ALS patients: An early and persistent phenomenon","volume":"256","author":"Bouteloup","year":"2009","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1126\/science.8209258","article-title":"Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation","volume":"264","author":"Gurney","year":"1994","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1002\/cne.21160","article-title":"Motor neuron degeneration in ALS mutant su-peroxide dismutase-1 transgenic mice: Mechanisms of mitochondriopathy and cell death","volume":"500","author":"Martin","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.expneurol.2009.02.015","article-title":"The mitochondrial permeability transition pore in motor neurons: Involvement in the pathobiology of ALS mice","volume":"218","author":"Martin","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00429-009-0226-4","article-title":"Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice","volume":"214","author":"Chen","year":"2009","journal-title":"Brain Struct. Funct."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Martin, L.J., Wong, M., and Hanaford, A. (2019). Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00635"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.drudis.2016.02.002","article-title":"A look into the future of ALS research","volume":"21","author":"Clerc","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1093\/hmg\/ddq106","article-title":"Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice","volume":"19","author":"Wong","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Martin, L.J., and Wong, M. (2020). Skeletal Muscle-Restricted Expression of Human SOD1 in Transgenic Mice Causes a Fatal ALS-Like Syndrome. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.592851"},{"key":"ref_14","first-page":"171","article-title":"Motor innervation of rodent diaphragm","volume":"149","author":"Comerford","year":"1986","journal-title":"J. Anat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1097\/nen.0b013e318158822b","article-title":"Adult olfactory bulb neural precursor cell grafts provide temporary protection from motor neuron de-generation, improve motor function, and extend survival in amyotrophic lateral sclerosis mice","volume":"66","author":"Martin","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1177\/0192623310389475","article-title":"An Approach to Experimental Synaptic Pathology Using Green Fluorescent Protein-Transgenic Mice and Gene Knockout Mice to Show Mitochondrial Permeability Transition Pore-Driven Excitotoxicity in Interneurons and Motoneurons","volume":"39","author":"Martin","year":"2010","journal-title":"Toxicol. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1006\/nbdi.2000.0314","article-title":"p53 is Abnormally Elevated and Active in the CNS of Patients with Amyotrophic Lateral Sclerosis","volume":"7","author":"Martin","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1046\/j.1471-4159.2003.01659.x","article-title":"Early events of target deprivation\/axotomy-induced neuronal apoptosis in vivo: Oxidative stress, DNA damage, p53 phosphorylation and subcellular redistribution of death proteins","volume":"85","author":"Martin","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Porter, G.A., Beutner, G., and Cyclophilin, D. (2018). somehow a master regulator to mitochondrial function. Biomolecules, 8.","DOI":"10.3390\/biom8040176"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.yjmcc.2009.02.007","article-title":"The molecular composition of the mitochondrial permeability transition pore","volume":"46","author":"Baines","year":"2009","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1056\/NEJMcps050929","article-title":"Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy","volume":"353","author":"Shankaran","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1056\/NEJMoa1112066","article-title":"Childhood Outcomes after Hypothermia for Neonatal Encephalopathy","volume":"366","author":"Shankaran","year":"2012","journal-title":"New Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1056\/NEJMoa1315788","article-title":"Effects of Hypothermia for Perinatal Asphyxia on Childhood Outcomes","volume":"371","author":"Azzopardi","year":"2014","journal-title":"New Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1159\/000369007","article-title":"Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets","volume":"37","author":"Zhu","year":"2015","journal-title":"Dev. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1742-2094-4-9","article-title":"Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant Cu\/Zn superoxide dismutase gene","volume":"4","author":"Fendrick","year":"2007","journal-title":"J. Neuroinflammation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"801","DOI":"10.3389\/fimmu.2019.00801","article-title":"Circulating cytokines could not be good prognostic biomarkers in a mouse model of amyotrophic lateral sclerosis","volume":"10","author":"Toivonen","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S178","DOI":"10.1086\/317513","article-title":"Circulating Cytokines as Mediators of Fever","volume":"31","author":"Netea","year":"2000","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/2985051","article-title":"Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNF\u03b1","volume":"2017","author":"Tortarolo","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.clnu.2020.07.029","article-title":"The clinical relevance and mechanism of skeletal muscle wasting","volume":"40","author":"Duan","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00424-016-1933-3","article-title":"Molecular mechanism of sarcopenia and cachexia: Recent research advances","volume":"469","author":"Sakuma","year":"2017","journal-title":"Pfl\u00fcgers Archiv \u2013 Eur. J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.cmet.2008.09.002","article-title":"Skeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity","volume":"8","author":"Dobrowolny","year":"2008","journal-title":"Cell Metab."},{"key":"ref_32","first-page":"749","article-title":"Thermoregulation in amyotrophic lateral sclerosis","volume":"Volume 157","author":"Romanovsky","year":"2018","journal-title":"Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11159","DOI":"10.1073\/pnas.0402026101","article-title":"Evidence for defective energy homeostasis in amyo-trophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model","volume":"101","author":"Dupuis","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/nan.12332","article-title":"Non-motor involvement in amyotrophic lateral sclerosis: New insight from nerve and vessel analysis in skin biopsy","volume":"43","author":"Nolano","year":"2017","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1212\/WNL.0b013e31821e553a","article-title":"Small-fiber neuropathy in patients with ALS","volume":"76","author":"Weis","year":"2011","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1111\/ene.12936","article-title":"Amyotrophic lateral sclerosis causes small fiber pathology","volume":"23","author":"Bella","year":"2016","journal-title":"Eur. J. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1136\/jnnp-2017-315795","article-title":"Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis","volume":"88","author":"Gorges","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.2741\/2011","article-title":"Response and function of skeletal muscle heat shock protein 70","volume":"11","author":"Liu","year":"2006","journal-title":"Front. Biosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13173","DOI":"10.1523\/JNEUROSCI.4057-07.2007","article-title":"Exogenous Delivery of Heat Shock Protein 70 Increases Lifespan in a Mouse Model of Amyotrophic Lateral Sclerosis","volume":"27","author":"Gifondorwa","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1471-4159.2012.07916.x","article-title":"Moderate hypothermia induces marked increase in levels and nuclear accumulation of SUMO2\/3-conjugated proteins in neurons","volume":"123","author":"Wang","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_41","first-page":"2242","article-title":"Genome maintenance in Saccharomyces cerevisiae: The role of SUMO and SUMO-targeted ubiquitin ligases","volume":"45","author":"Jalal","year":"2017","journal-title":"Nucleic Acid Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1136\/jnnp.37.9.1036","article-title":"Motor neurone disease: The nature of the pathogenic mechanism","volume":"37","author":"Mann","year":"1974","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1001\/archneur.1982.00510230003001","article-title":"A New Hypothesis of the Etiology of Amyotrophic Lateral Sclerosis","volume":"39","author":"Bradley","year":"1982","journal-title":"Arch. Neurol."},{"key":"ref_44","first-page":"797","article-title":"Evidence for DNA damage in amyotrophic lateral sclerosis","volume":"19","author":"Fitzmaurice","year":"1996","journal-title":"Muscle Nerve"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/NEN.0b013e31816ff780","article-title":"DNA damage and repair: Relevance to mechanisms of neurodegeneration","volume":"67","author":"Martin","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40478-019-0874-4","article-title":"DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations","volume":"8","author":"Kim","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.expneurol.2003.10.004","article-title":"Amyotrophic lateral sclerosis is a distal axonopathy: Evidence in mice and man","volume":"185","author":"Fischer","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.mad.2016.06.011","article-title":"Enforced DNA repair enzymes rescue neurons from apoptosis induced by target deprivation and axotomy in mouse models of neurodegeneration","volume":"161","author":"Martin","year":"2017","journal-title":"Mech. Ageing Dev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4103\/1817-1745.181269","article-title":"Effect of therapeutic hypothermia on chromosomal aberration in perinatal asphyxia","volume":"11","author":"Bhat","year":"2016","journal-title":"J. Pediatr. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fneur.2013.00086","article-title":"Enhanced Uncoupling of the Mitochondrial Respiratory Chain as a Potential Source for Amyotrophic Lateral Sclerosis","volume":"4","author":"Hoffmann","year":"2013","journal-title":"Front. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"16258","DOI":"10.1074\/jbc.M910179199","article-title":"Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice","volume":"275","author":"Grujic","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S130","DOI":"10.2337\/diabetes.53.2007.S130","article-title":"The biology of mi-tochondrial uncoupling proteins","volume":"53","author":"Rousset","year":"2004","journal-title":"Diabetes"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.bbabio.2010.02.033","article-title":"Cold tolerance of UCP1-ablated mice: A skeletal muscle mitochondria switch toward lipid oxidation with marked UCP3 up-regulation not associated with increased basal, fatty acid- or ROS-induced uncoupling or enhanced GDP effects","volume":"1797","author":"Shabalina","year":"2010","journal-title":"Biochim. et Biophys. Acta (BBA)\u2014Bioenerg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.bbabio.2009.12.006","article-title":"Cyclophilin D in mitochondrial pathobi-ology","volume":"1997","author":"Giorgio","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3389\/fncel.2014.00433","article-title":"GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis","volume":"8","author":"Martin","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00395-017-0624-3","article-title":"Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition","volume":"112","author":"Jahandiez","year":"2017","journal-title":"Basic Res. Cardiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/2\/320\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:20:07Z","timestamp":1760160007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/2\/320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,4]]},"references-count":56,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["cells10020320"],"URL":"https:\/\/doi.org\/10.3390\/cells10020320","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,4]]}}}