|
||
ARTICLE |
Correspondence to Robert T. Dirksen: Robert_Dirksen{at}URMC.Rochester.edu
Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)250 repeats (HSALR mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 13-wk-old wild-type and HSALR mice. The results indicate that peak ClC-1 current density at 140 mV is reduced >70% (48.5 ± 3.6 and 14.0 ± 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 1820- d-old HSALR mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSALR FDB fibers results from a large reduction in ClC-1 channel density (170 ± 21 and 58 ± 11 channels/pF in control and HSALR fibers, respectively) and a modest decrease in maximal channel open probability(0.91 ± 0.01 and 0.75 ± 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1
E3/
E3), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeatcontaining mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.
This article has been cited by other articles:
![]() |
T. H. Pedersen, F. V. de Paoli, J. A. Flatman, and O. B. Nielsen Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers J. Gen. Physiol., October 1, 2009; 134(4): 309 - 322. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. H. Pedersen, W. A. Macdonald, F. V. de Paoli, I. S. Gurung, and O. B. Nielsen Comparison of regulated passive membrane conductance in action potential-firing fast- and slow-twitch muscle J. Gen. Physiol., October 1, 2009; 134(4): 323 - 337. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Kino, C. Washizu, Y. Oma, H. Onishi, Y. Nezu, N. Sasagawa, N. Nukina, and S. Ishiura MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1 Nucleic Acids Res., October 1, 2009; 37(19): 6477 - 6490. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. M. Wheeler, K. Sobczak, J. D. Lueck, R. J. Osborne, X. Lin, R. T. Dirksen, and C. A. Thornton Reversal of RNA Dominance by Displacement of Protein Sequestered on Triplet Repeat RNA Science, July 17, 2009; 325(5938): 336 - 339. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. J. Osborne, X. Lin, S. Welle, K. Sobczak, J. R. O'Rourke, M. S. Swanson, and C. A. Thornton Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy Hum. Mol. Genet., April 15, 2009; 18(8): 1471 - 1481. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Boncompagni, A. E. Rossi, M. Micaroni, G. V. Beznoussenko, R. S. Polishchuk, R. T. Dirksen, and F. Protasi Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures Mol. Biol. Cell, February 1, 2009; 20(3): 1058 - 1067. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Zifarelli and M. Pusch The Muscle Chloride Channel ClC-1 Is Not Directly Regulated by Intracellular ATP J. Gen. Physiol., February 1, 2008; 131(2): 109 - 116. [Abstract] [Full Text] [PDF] |
||||
|
|