{"doi":"10.1085/jgp.202012637","title":"A mouse model of Huntington’s disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers","abstract":"Huntington's disease (HD) is a fatal and progressive condition with severe debilitating motor defects and muscle weakness. 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-contraction (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's disease.","journal":"The Journal of General Physiology","year":2021,"id":192753,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":759976,"name":"Sabrina Metzger","orcid":"0000-0003-1655-0544","position":1,"is_corresponding":false},{"id":384559,"name":"Kristiana Peraza","orcid":null,"position":2,"is_corresponding":false},{"id":759977,"name":"Matthew C. Wright","orcid":"0000-0003-3167-6743","position":3,"is_corresponding":false},{"id":759978,"name":"D. Scott Jobe","orcid":"0000-0002-4495-6122","position":4,"is_corresponding":false},{"id":299279,"name":"Long‐Sheng Song","orcid":"0000-0002-6035-8106","position":5,"is_corresponding":false},{"id":402519,"name":"Mark M. Rich","orcid":"0000-0002-6956-5531","position":6,"is_corresponding":false},{"id":759979,"name":"Brent D. Foy","orcid":"0000-0003-4480-5049","position":7,"is_corresponding":false},{"id":402517,"name":"Robert J. Talmadge","orcid":"0000-0002-8792-3312","position":8,"is_corresponding":false},{"id":402518,"name":"Andrew A. Voss","orcid":"0000-0001-7530-6272","position":9,"is_corresponding":false},{"id":703463,"name":"Shannon H. Romer","orcid":"0000-0002-0211-6926","position":0,"is_corresponding":true}],"reference_count":97,"raw_metadata":null,"created_at":"2026-07-18T23:49:43.496702Z","pmid":"33683318","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}