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Through activation of peripheral cold receptors (e.g. TRPM8), CWI triggers sympathetic noradrenaline release and hypothalamic\u2013pituitary\u2013thyroid axis stimulation (TSH\u2192D2\u2192T3), driving \u03b2\u2010adrenergic\/cAMP\u2013PKA\u2013p38MAPK\u2013CREB signalling that could robustly upregulate PGC\u20101\u03b1 and uncoupling protein\u20101 in brown adipose tissue and skeletal muscle. Concurrent shivering\u2010induced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    fluxes engage calcium\/calmodulin\u2010stimulated protein kinase II and calcineurin, enhancing PGC\u20101\u03b1 expression in an AMP\u2010activated protein kinase (AMPK)\u2010independent manner. Elevated PGC\u20101\u03b1 coactivates nuclear respiratory factors (NRF1\/NRF2) and mitochondrial transcription factor A to expand mitochondrial content and oxidative capacity, while upregulating key antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase). Together with oestrogen\u2010related receptor \u03b1, PGC\u20101\u03b1 can co\u2010activate vascular endothelial growth factor, a pathway compatible with angiogenesis and improved perfusion; however, in humans the link to CWI remains indirect and is largely limited to acute molecular responses. Downstream metabolic adaptations, including increased fatty acid oxidation (via carnitine palmitoyltransferase 1, peroxisome proliferator\u2010activated receptors \u03b1\/\u03b3 and AMPK) and fibroblast growth factor 21 secretion, enhance insulin sensitivity and energy expenditure. Most of the evidence currently rests on molecular signalling data, heterogeneous study designs, or acute gene expression responses. Direct evidence for increased mitochondrial content, improved mitochondrial function, or long\u2010term health benefits in humans is scarce. Therefore, this article introduces a hypothetical dose\u2013response relationship, linking immersion time to proposed health benefits and death, and provides practical recommendations for safe CWI protocols.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70202-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1113\/jp289536","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T18:54:30Z","timestamp":1761764070000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Potential health benefits of cold\u2010water immersion: the central role of PGC\u20101\u03b1"],"prefix":"10.1113","author":[{"given":"Erich","family":"Hohenauer","sequence":"first","affiliation":[{"name":"Department of Business Economics, Health, and Social Care, SUPSI Landquart University of Applied Sciences and Arts of Southern Switzerland  Landquart Switzerland"},{"name":"Laboratoire Mobilit\u00e9 Vieillissement et Exercice (MOVE) \u2013 UR 20296, Faculty of Sports Sciences University of Poitiers Poitiers France"},{"name":"Department of Movement and Sport Sciences University of Fribourg  Fribourg Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wafa","family":"Douzi","sequence":"additional","affiliation":[{"name":"Department of Business Economics, Health, and Social Care, SUPSI Landquart University of Applied Sciences and Arts of Southern Switzerland  Landquart Switzerland"},{"name":"Laboratoire Mobilit\u00e9 Vieillissement et Exercice (MOVE) \u2013 UR 20296, Faculty of Sports Sciences University of Poitiers Poitiers France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Burtscher","sequence":"additional","affiliation":[{"name":"Department of Sport Science University of Innsbruck  Innsbruck Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12051075"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP087718"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-022-04915-5"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00096.2017"},{"key":"e_1_2_2_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4615"},{"key":"e_1_2_2_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06613"},{"key":"e_1_2_2_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2006.03.003"},{"key":"e_1_2_2_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2014.121"},{"key":"e_1_2_2_10_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0367com"},{"key":"e_1_2_2_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-201X.2003.01185.x"},{"key":"e_1_2_2_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01040.2011"},{"key":"e_1_2_2_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00498.2012"},{"key":"e_1_2_2_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtherbio.2023.103775"},{"key":"e_1_2_2_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1400-3"},{"key":"e_1_2_2_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00002.2015"},{"key":"e_1_2_2_17_1","doi-asserted-by":"publisher","DOI":"10.2147\/OAJSM.S41655"},{"key":"e_1_2_2_18_1","article-title":"Cold\u2010water immersion (cryotherapy) for preventing and treating muscle soreness after exercise","volume":"2","author":"Bleakley C.","year":"2012","journal-title":"The Cochrane Database of Systematic Reviews"},{"key":"e_1_2_2_19_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP273395"},{"key":"e_1_2_2_20_1","first-page":"153","volume-title":"Handbook of clinical neurology","author":"Blondin D. 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