Age‐dependent chloride channel expression in skeletal muscle fibres of normal and HSALR myotonic mice

Key points • The role that the age-dependent expression of chloride channels (ClC-1) plays on the electrical properties of muscle fibres from normal and human skeletal actin (HSA)LR mice (a model of myotonic dystrophy) was studied using a combination of electrophysiological and optical techniques. • Chloride currents (ICl) are significantly smaller in fibres isolated from young (2 weeks old) HSALR mice than from aged-matched control mice, but become statistically undistinguishable in adult (17 weeks old) mice. Thus, the severe ClC-1 channelopathy in young HSALR animals slowly reverses with aging. • The maximal chloride conductance (gCl,max) is uniformly depressed in fibres of young HSALR mice, but fibres from older animals show a wide range of gCl,max values suggestive of a mosaic expression of ClC-1 channels in FDB muscles of these animals. • Regardless of the age of the animals, the chloride channelopathy does not affect the normal expression of ClC-1 channels at the sarcolemma and transverse tubular system membranes. • The membrane resistance (Rm) is lower than expected in young HSALR animals due to an upregulation of an Rb-sensitive K conductance. In adult animals, differences in Rm are negligible between fibres of both animal strains. • It is proposed that, while the hyperexcitability in young HSALR mice can be accounted for by the reduction in gCl,max, a mosaic expression of ClC-1 channels and/or alterations of other conductances may be the underlying causes in adult animals. 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 HSALR 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 HSALR animals is slowly reversed with aging. Frequency histograms of the maximal chloride conductance (gCl,max) in fibres of young HSALR 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 HSALR 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 HSALR animals. We surmise that while hyperexcitability in young HSALR mice can be readily explained on the basis of reduced gCl, myotonia in adult HSALR 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.