{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:14:15Z","timestamp":1790709255809,"version":"4.1.0"},"reference-count":179,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR)","doi-asserted-by":"publisher","award":["PJT-162172"],"award-info":[{"award-number":["PJT-162172"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Manitoba","award":["PJT-162172"],"award-info":[{"award-number":["PJT-162172"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca2+ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M1R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M1R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca2+-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M1R. TRPM3 activation enhanced mitochondrial Ca2+ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca2+ signaling imbalances in DSPN and presents M1R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies.<\/jats:p>","DOI":"10.3390\/ijms26157393","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"7393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Muscarinic Receptor Antagonism and TRPM3 Activation as Stimulators of Mitochondrial Function and Axonal Repair in Diabetic Sensorimotor Polyneuropathy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6259-3283","authenticated-orcid":false,"given":"Sanjana","family":"Chauhan","sequence":"first","affiliation":[{"name":"Division of Neurodegenerative & Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, Canada"},{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0T6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel A.","family":"Calcutt","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9507-1201","authenticated-orcid":false,"given":"Paul","family":"Fernyhough","sequence":"additional","affiliation":[{"name":"Division of Neurodegenerative & Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, Canada"},{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0T6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1016\/j.neuron.2023.05.003","article-title":"New perspectives in diabetic neuropathy","volume":"111","author":"Eid","year":"2023","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/s41574-021-00496-z","article-title":"Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy","volume":"17","author":"Sloan","year":"2021","journal-title":"Nat. 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