Dataset Information

Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation.

ABSTRACT: UNLABELLED:Loss of Muscleblind-like 1 (Mbnl1) is known to alter Clc-1 splicing to result in myotonia. Mbnl1(?E3/?E3)/Mbnl3(?E2) mice, depleted of Mbnl1 and Mbnl3, demonstrate a profound enhancement of myotonia and an increase in the number of muscle fibers with very low Clc-1 currents, where gClmax values approach ~ 1 mS/cm(2), with the absence of a further enhancement in Clc-1 splice errors, alterations in polyA site selection or Clc-1 localization. Significantly, Mbnl1(?E3/?E3)/Mbnl3(?E2) muscles demonstrate an aberrant accumulation of Clc-1 RNA on monosomes and on the first polysomes. Mbnl1 and Mbnl3 bind Clc-1 RNA and both proteins bind Hsp70 and eEF1A, with these associations being reduced in the presence of RNA. Thus binding of Mbnl1 and Mbnl3 to Clc-1 mRNA engaged with ribosomes can facilitate an increase in the local concentration of Hsp70 and eEF1A to assist Clc-1 translation. Dual depletion of Mbnl1 and Mbnl3 therefore initiates both Clc-1 splice errors and translation defects to synergistically enhance myotonia. As the HSA(LR) model for myotonic dystrophy (DM1) shows similar Clc-1 defects, this study demonstrates that both splice errors and translation defects are required for DM1 pathology to manifest. RESEARCH IN CONTEXT:Research in context: Myotonic Dystrophy type 1 (DM1) is a dominant disorder resulting from the expression of expanded CUG repeat RNA, which aberrantly sequesters and inactivates the muscleblind-like (MBNL) family of proteins. In mice, inactivation of Mbnl1 is known to alter Clc-1 splicing to result in myotonia. We demonstrate that concurrent depletion of Mbnl1 and Mbnl3 results in a synergistic enhancement of myotonia, with an increase in muscle fibers showing low chloride currents. The observed synergism results from the aberrant accumulation of Clc-1 mRNA on monosomes and the first polysomes. This translation error reflects the ability of Mbnl1 and Mbnl3 to act as adaptors that recruit Hsp70 and eEF1A to the Clc-1 mRNA engaged with ribosomes, to facilitate translation. Thus our study demonstrates that Clc-1 RNA translation defects work coordinately with Clc-1 splice errors to synergistically enhance myotonia in mice lacking Mbnl1 and Mbnl3.

SUBMITTER: Choi J

PROVIDER: S-EPMC4588380 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation.

Choi Jongkyu J Personius Kirkwood E KE DiFranco Marino M Dansithong Warunee W Yu Carl C Srivastava Saumya S Dixon Donald M DM Bhatt Darshan B DB Comai Lucio L Vergara Julio L JL Reddy Sita S

EBioMedicine 20150731 9

Loss of Muscleblind-like 1 (Mbnl1) is known to alter Clc-1 splicing to result in myotonia. Mbnl1(ΔE3/ΔE3)/Mbnl3(ΔE2) mice, depleted of Mbnl1 and Mbnl3, demonstrate a profound enhancement of myotonia and an increase in the number of muscle fibers with very low Clc-1 currents, where gClmax values approach ~ 1 mS/cm(2), with the absence of a further enhancement in Clc-1 splice errors, alterations in polyA site selection or Clc-1 localization. Significantly, Mbnl1(ΔE3/ΔE3)/Mbnl3(ΔE2) muscles demonst ...[more]

PMID: 26501102

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Project description:The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

Dataset Information

Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation.

Publications

Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation.

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