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The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long\u2010term post\u2010synaptic neuromuscular blockade.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sprague Dawley rats were subjected to post\u2010synaptic blockade of neuromuscular transmission by systemic administration of \u03b1\u2010cobrotoxin and mechanically ventilated for up to 8\u00a0days and compared with untreated sham operated controls and animals exposed to unilateral chronic electrical stimulation 12\u00a0h\/day for 5 or 8\u00a0days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NMJs produced axonal and glial sprouts (growth of processes that extend beyond the confines of the synapse defined by high\u2010density aggregates of acetylcholine receptors [AChRs]) in response to post\u2010synaptic neuromuscular blockade, but less than reported after peripheral denervation or pre\u2010synaptic blockade. Direct electrical soleus muscle stimulation reduced the terminal Schwann cell (tSC) and axonal sprouting in both stimulated and non\u2010stimulated contralateral soleus. Eight days chronic stimulation reduced (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) the number of tSC sprouts on stimulated and non\u2010stimulated soleus from 6.7\u00a0\u00b1\u00a00.5 and 6.9\u00a0\u00b1\u00a00.5 sprouts per NMJ, respectively, compared with 10.3\u00a0\u00b1\u00a00.9 tSC per NMJ (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) in non\u2010stimulated soleus from rats immobilized for 8\u00a0days. A similar reduction of axonal sprouts (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) was observed in stimulated and non\u2010stimulated contralateral soleus in response to chronic electrical stimulation. RNAseq\u2010based gene expression analyses confirmed a restoring effect on both stimulated and unstimulated contralateral muscle. The cross\u2010over effect was paralleled by increased cytokine\/chemokine levels in stimulated and contralateral unstimulated muscle as well as in plasma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Motor axon terminals and terminal Schwann cells at NMJs of rats subjected to post\u2010synaptic neuromuscular blockade exhibited sprouting responses. These axonal and glial responses were likely dampened by a muscle\u2010derived myokines released in an activity\u2010dependent manner with both local and systemic effects.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13235","type":"journal-article","created":{"date-parts":[[2023,4,15]],"date-time":"2023-04-15T09:13:46Z","timestamp":1681550026000},"page":"1533-1545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4993-9038","authenticated-orcid":false,"given":"Young il","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Biology Texas A&amp;M University  College Station TX USA"},{"name":"Department of Pharmacology &amp; Therapeutics, College of Medicine, University of Florida Myology 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Muscle Biology Group Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Biology Texas A&amp;M University  College Station TX USA"},{"name":"Section of Molecular Cell and Developmental Biology The University of Texas  Austin TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3722-035X","authenticated-orcid":false,"given":"Lars","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Basic and Clinical Muscle Biology Group Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Clinical Neuroscience, Section of Clinical Neurophysiology Karolinska Institutet  Stockholm Sweden"},{"name":"Viron Molecular Medicine Institute  Boston MA 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