Journal article
A mouse model of Huntington's disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers
The Journal of general physiology, Vol.153(4), p.1
04/05/2021
DOI: 10.1085/jgp.202012637
PMCID: PMC7931643
PMID: 33683318
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.
Details
- Title: Subtitle
- A mouse model of Huntington's disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers
- Creators
- Shannon H. Romer - Wright State UniversitySabrina Metzger - Wright State UniversityKristiana Peraza - California State Polytechnic UniversityMatthew C. Wright - California State Polytechnic UniversityD. Scott Jobe - Wright State UniversityLong-Sheng Song - Wright State UniversityMark M. Rich - Wright State UniversityBrent D. Foy - Wright State UniversityRobert J. Talmadge - California State Polytechnic UniversityAndrew A. Voss - Wright State University
- Resource Type
- Journal article
- Publication Details
- The Journal of general physiology, Vol.153(4), p.1
- DOI
- 10.1085/jgp.202012637
- PMID
- 33683318
- PMCID
- PMC7931643
- NLM abbreviation
- J Gen Physiol
- ISSN
- 0022-1295
- eISSN
- 1540-7748
- Publisher
- Rockefeller Univ Press
- Number of pages
- 21
- Grant note
- R15NS099850 / National Institutes of Health/National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) AR074985 / National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS)
- Language
- English
- Date published
- 04/05/2021
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984293082302771
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