Dystrophin is absent in the muscle fibers of patients with Duchenne muscular dystrophy (DMD) and also in muscle fibers from the mdx mouse, an animal model of DMD. Disrupted excitation-contraction (E-C) coupling has been postulated to be a functional consequence of the lack of dystrophin, although the evidence for this is not entirely clear. We used mechanically skinned fibers (with a sealed transverse-tubular (T-) system) prepared from fast extensor digitorum longus (EDL) muscles of wild-type control and dystrophic mdx mice to test the hypothesis that dystrophin deficiency would affect the depolarization-induced contractile response (DICR) and sarcoplasmic reticulum (SR) function. DICR was similar in muscle fibers from mdx and control mice, indicating normal voltage regulation of Ca²⁺ release. Nevertheless, rundown of DICR (< 50% of initial) was reached more rapidly in fibers from mdx than control mice [control: 32 ± 5 depolarizations (n = 14 fibers) vs. mdx: 18 ± 1 depolarizations (n = 7) before rundown, P < 0.05]. The repriming rate for DICR's was decreased in fibers from mdx mice, with lower submaximal DICR observed following 5, 10 and 20s of repriming compared with fibers from control mice (P<0.05). SR Ca²⁺ reloading was not different in fibers from control and mdx mice, nor was any difference observed in SR Ca²⁺ leak. Caffeine (2-7 mM)-induced contraction was diminished in fibers from mdx mice compared to control (P < 0.05), indicating depressed SR Ca²⁺ release channel activity. Our findings indicate that fast fibers from mdx mice exhibit some impairment in the events mediating E-C coupling and SR Ca²⁺ release channel activity.