Age‐dependent chloride channel expression in skeletal muscle fibres of normal and HSA^LR myotonic mice

Abstract

We combine electrophysiological and optical techniques to investigate the role that the expression of chloride channels (ClC-1) plays on the age-dependent electrical properties of mammalian muscle fibres. To this end, we comparatively evaluate the magnitude and voltage dependence of chloride currents (ICl), as well as the resting resistance, in fibres isolated from control and human skeletal actin (HSA)(LR) mice (a model of myotonic dystrophy) of various ages. In control mice, the maximal peak chloride current ([peak-ICl]max) increases from -583 ± 126 to -956 ± 260 μA cm(-2) (mean ± SD) between 3 and 6 weeks old. Instead, in 3-week-old HSA(LR) mice, ICl are significantly smaller (-153 ± 33 μA cm(-2)) than in control mice, but after a long period of ∼14 weeks they reach statistically comparable values. Thus, the severe ClC-1 channelopathy in young HSA(LR) animals is slowly reversed with aging. Frequency histograms of the maximal chloride conductance (gCl,max) in fibres of young HSA(LR) animals are narrow and centred in low values; alternatively, those from older animals show broad distributions, centred at larger gCl,max values, compatible with mosaic expressions of ClC-1 channels. In fibres of both animal strains, optical data confirm the age-dependent increase in gCl, and additionally suggest that ClC-1 channels are evenly distributed between the sarcolemma and transverse tubular system membranes. Although gCl is significantly depressed in fibres of young HSA(LR) mice, the resting membrane resistance (Rm) at -90 mV is only slightly larger than in control mice due to upregulation of a Rb-sensitive resting conductance (gK,IR). In adult animals, differences in Rm are negligible between fibres of both strains, and the contributions of gCl and gK,IR are less altered in HSA(LR) animals. We surmise that while hyperexcitability in young HSA(LR) mice can be readily explained on the basis of reduced gCl, myotonia in adult HSA(LR) animals may be explained on the basis of a mosaic expression of ClC-1 channels in different fibres and/or on alterations of other conductances.

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

“…Taken together our data demonstrate that Mbnl1 and Mbnl3 deficits profoundly enhance myotonia and that the mechanisms driving this enhancement are not only Clc-1 splice errors resulting from Mbnl1 loss, but also Clc-1 translation defects occurring from the dual loss of Mbnl1 and Mbnl3. Importantly, as both Clc-1 splice defects and an aberrant accumulation of Clc-1 RNA on monosomes and the first polysomes is observed in the HSA LR DM1 model, where a similar increase in a subpopulation of muscle fibers with low chloride currents has been reported ( DiFranco et al, 2013 ), our data demonstrate that splice defects work coordinately with translation errors for key features of myotonic dystrophy pathology to fully manifest.…”

A mouse model of Huntington’s disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers

“…Previously, we found an early-onset and progressive reduction in R6/2 muscle fiber capacitance normalized to sarcolemma membrane surface area ( C m,S , µF/cm 2 ) compared with controls beyond that expected for the disease-related reduction in muscle fiber size ( DiFranco et al, 2013 ; Waters et al, 2013 ; Miranda et al, 2017 ). This decrease in C m.S was likely due to a partial loss or disruption of the t-tubule system (TTS).…”

Inward rectifier potassium currents in mammalian skeletal muscle fibres

“…; DiFranco et al . ); and (3) g Kir max depends on the bulk [K + ] o (Almers, ; Hagiwara & Takahashi, ; Hagiwara & Yoshii, ; Leech & Stanfield, ; Stanfield et al . ).…”