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Peroxisome proliferator\u2013activated receptor-\u03b3 coactivator-1\u03b1 (PGC-1\u03b1) is a regulator of mitochondrial function in multiple cell types. In sensory neurons, AMP-activated protein kinase (AMPK) augments PGC-1\u03b1 activity and this pathway is depressed in diabetes leading to mitochondrial dysfunction and neurodegeneration. Antimuscarinic drugs targeting the muscarinic acetylcholine type 1 receptor (M<jats:sub>1<\/jats:sub>R) prevent\/reverse neurodegeneration by inducing nerve regeneration in rodent models of diabetes and chemotherapy-induced peripheral neuropathy (CIPN). Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase kinase \u03b2 (CaMKK\u03b2) is an upstream regulator of AMPK activity. We <jats:italic>hypothesized<\/jats:italic> that antimuscarinic drugs modulate CaMKK\u03b2 to enhance activity of AMPK, and PGC-1\u03b1, increase mitochondrial function and thus protect from neurodegeneration. We used the specific M<jats:sub>1<\/jats:sub>R antagonist muscarinic toxin 7 (MT7) to manipulate muscarinic signaling in the dorsal root ganglia (DRG) neurons of normal rats or rats with streptozotocin-induced diabetes. DRG neurons treated with MT7 (100\u00a0nM) or a selective muscarinic antagonist, pirenzepine (1\u00a0\u03bcM), for 24\u00a0h showed increased neurite outgrowth that was blocked by the CaMKK inhibitor STO-609 (1\u00a0\u03bcM) or short hairpin RNA to CaMKK\u03b2. MT7 enhanced AMPK phosphorylation which was blocked by STO-609 (1\u00a0\u03bcM). PGC-1\u03b1 reporter activity was augmented up to 2-fold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) by MT7 and blocked by STO-609. Mitochondrial maximal respiration and spare respiratory capacity were elevated after 3\u00a0h of exposure to MT7 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Diabetes and CIPN induced a significant (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) decrease in corneal nerve density which was corrected by topical delivery of MT7. We reveal a novel M<jats:sub>1<\/jats:sub>R-modulated, CaMKK\u03b2-dependent pathway in neurons that represents a therapeutic target to enhance nerve repair in two of the most common forms of peripheral neuropathy.<\/jats:p>","DOI":"10.1007\/s12035-020-01900-x","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T12:02:50Z","timestamp":1584705770000},"page":"2521-2538","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Muscarinic Toxin 7 Signals Via Ca2+\/Calmodulin-Dependent Protein Kinase Kinase \u03b2 to Augment Mitochondrial Function and Prevent Neurodegeneration"],"prefix":"10.1007","volume":"57","author":[{"given":"Ali","family":"Saleh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Golam","family":"Sabbir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad-Reza","family":"Aghanoori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell R.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subir K.","family":"Roy Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Tessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Gedarevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markos Z.","family":"Kassahun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Frizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel A.","family":"Calcutt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Fernyhough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,20]]},"reference":[{"issue":"4","key":"1900_CR1","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1177\/10738584070130040901","volume":"13","author":"KM Albers","year":"2007","unstructured":"Albers KM, Davis BM (2007) The skin as a neurotrophic organ. 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This IP includes some of\u00a0the data presented in the current manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}