A Mouse Model of Huntington’s Disease Shows Altered Ultrastructure of Transverse Tubules in Skeletal Muscle Fibers
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.
Romer, S. H.,
Wright, M. C.,
Jobe, D. S.,
Rich, M. M.,
Foy, B. D.,
Talmadge, R. J.,
& Voss, A. A.
(2021). A Mouse Model of Huntington’s Disease Shows Altered Ultrastructure of Transverse Tubules in Skeletal Muscle Fibers. Journal of General Physiology, 153 (4).
Medical Cell Biology Commons, Medical Neurobiology Commons, Medical Physiology Commons, Neurosciences Commons, Physiological Processes Commons
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.