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Although classically recognized as a neurodegenerative disorder, there is increasing evidence of cell autonomous toxicity in skeletal muscle. We recently demonstrated that skeletal muscle fibers from the R6\/2 model mouse of HD have a decrease in specific membrane capacitance, suggesting a loss of transverse tubule (t-tubule) membrane in R6\/2 muscle. A previous report also indicated that Cav1.1 current was reduced in R6\/2 skeletal muscle, suggesting defects in excitation\u2013contraction (EC) coupling. Thus, we hypothesized that a loss and\/or disruption of the skeletal muscle t-tubule system contributes to changes in EC coupling in R6\/2 skeletal muscle. We used live-cell imaging with multiphoton confocal microscopy and transmission electron microscopy to assess the t-tubule architecture in late-stage R6\/2 muscle and found no significant differences in the t-tubule system density, regularity, or integrity. However, electron microscopy images revealed that the cross-sectional area of t-tubules at the triad were 25% smaller in R6\/2 compared with age-matched control skeletal muscle. Computer simulation revealed that the resulting decrease in the R6\/2 t-tubule luminal conductance contributed to, but did not fully explain, the reduced R6\/2 membrane capacitance. Analyses of bridging integrator-1 (Bin1), which plays a primary role in t-tubule formation, revealed decreased Bin1 protein levels and aberrant splicing of Bin1 mRNA in R6\/2 muscle. Additionally, the distance between the t-tubule and sarcoplasmic reticulum was wider in R6\/2 compared with control muscle, which was associated with a decrease in junctophilin 1 and 2 mRNA levels. Altogether, these findings can help explain dysregulated EC coupling and motor impairment in Huntington\u2019s disease.<\/jats:p>","DOI":"10.1085\/jgp.202012637","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T15:07:16Z","timestamp":1615216036000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["A mouse model of Huntington\u2019s disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers"],"prefix":"10.1085","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0211-6926","authenticated-orcid":true,"given":"Shannon H.","family":"Romer","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Wright State University, Dayton, OH 1"},{"name":"Odyssey Systems, Environmental Health Effects Laboratory, Navy Medical Research Unit, Dayton, Wright-Patterson Air Force Base, Dayton, OH 5"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-0544","authenticated-orcid":true,"given":"Sabrina","family":"Metzger","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cell Biology, and Physiology, Wright State University, Dayton, OH 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristiana","family":"Peraza","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, California State Polytechnic University, Pomona, Pomona, CA 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, California State Polytechnic University, Pomona, Pomona, CA 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-6122","authenticated-orcid":true,"given":"D. Scott","family":"Jobe","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Wright State University, Dayton, OH 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long-Sheng","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 4"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-5531","authenticated-orcid":true,"given":"Mark M.","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cell Biology, and Physiology, Wright State University, Dayton, OH 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-5049","authenticated-orcid":true,"given":"Brent D.","family":"Foy","sequence":"additional","affiliation":[{"name":"Department of Physics, Wright State University, Dayton, OH 6"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8792-3312","authenticated-orcid":true,"given":"Robert J.","family":"Talmadge","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, California State Polytechnic University, Pomona, Pomona, CA 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7530-6272","authenticated-orcid":true,"given":"Andrew A.","family":"Voss","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Wright State University, Dayton, OH 1"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"2023072706142215000_bib1","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1113\/jphysiol.1974.sp010499","article-title":"Membrane capacity measurements on frog skeletal muscle in media of low ion content","volume":"237","author":"Adrian","year":"1974","journal-title":"J. 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