The transgenic mouse HSALR has been proposed as a model for myotonic dystrophy type 1, capable of recapitulating the human pathology, including the loss of chloride currents (ICl). Since the structural organization of the transverse tubular system (TTS) is not completed until ∼3 weeks after birth, and the functional expression of ClC-1 channels may depend on this, we wanted to investigate whether the reduction of ICl in HSALR animals, compared to that in normal controls, changes with age. To this end, we performed a longitudinal study of the evolution of ICl and TTS voltage transients (using the potentiometric dye di-8-ANEPPS) in fibers from 2, 3, 4, 16 and 26 weeks old animals. ICl and optical signals were simultaneously acquired in fibers under voltage-clamp conditions using a 3-pulse protocol and a 2-microelectrode system. The fibers were bathed in 156 mM TEA-Cl and internally equilibrated with 70 mM Cl. The characteristics of ICl, and their effects on di-8-ANEPPS transients, were predicted using a radial cable model of the TTS. Our results show that, whereas fibers from 2-week old HSALR mice displayed peak ICl (for a −120 mV pulse) of −110±50 μA/cm2 (n=8), their control counterparts’ were −510±80 μA/cm2 (n=6). Furthermore, the magnitude of ICl increases with age in both animal strains, and by 16 weeks they reach similar levels (>750 μA/cm2). Thus, a reduction in ICl is significant in very young HSALR specimens, but not apparent in mature animals. We also verified that in HSALR animals the gain in total ICl with age is accompanied by the expression of functional ClC-1 channels in the TTS system. This work was supported by NIH grants AR047664, AR041802, and AR054816. HSALR mice were kindly provided by Dr. C. Thornton, University of Rochester.