{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:01:17Z","timestamp":1791529277150,"version":"4.3.4"},"reference-count":107,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Unaccustomed and\/or strenuous eccentric contractions are known to cause delayed-onset muscle soreness. In spite of this fact, their exact cause and mechanism have been unknown for more than 120 years. The exploration of the diverse functionality of the Piezo2 ion channel, as the principal proprioceptive component, and its autonomously acquired channelopathy may bring light to this apparently simple but mysterious pain condition. Correspondingly, the neurocentric non-contact acute compression axonopathy theory of delayed-onset muscle soreness suggests two damage phases affecting two muscle compartments, including the intrafusal (within the muscle spindle) and the extrafusal (outside the muscle spindle) ones. The secondary damage phase in the extrafusal muscle space is relatively well explored. However, the suggested primary damage phase within the muscle spindle is far from being entirely known. The current manuscript describes how the proposed autonomously acquired Piezo2 channelopathy-induced primary damage could be the initiating transient neural switch in the unfolding of delayed-onset muscle soreness. This primary damage results in a transient proprioceptive neural switch and in a switch from quantum mechanical free energy-stimulated ultrafast proton-coupled signaling to rapid glutamate-based signaling along the muscle\u2013brain axis. In addition, it induces a transient metabolic switch or, even more importantly, an energy generation switch in Type Ia proprioceptive terminals that eventually leads to a transient glutaminolysis deficit and mitochondrial deficiency, not to mention a force generation switch. In summary, the primary damage or switch is likely an inward unidirectional proton pathway reversal between Piezo2 and its auxiliary ligands, leading to acquired Piezo2 channelopathy.<\/jats:p>","DOI":"10.3390\/ijms26052319","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T07:56:52Z","timestamp":1741161412000},"page":"2319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Delayed-Onset Muscle Soreness Begins with a Transient Neural Switch"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-1306","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Sonkodi","sequence":"first","affiliation":[{"name":"Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1123 Budapest, Hungary"},{"name":"Department of Sports Medicine, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.2165\/00007256-200333020-00005","article-title":"Delayed onset muscle soreness: Treatment strategies and performance factors","volume":"33","author":"Cheung","year":"2003","journal-title":"Sports Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Berkes, I., and Koltai, E. 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