Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by the absence of functional dystrophin. Abnormal excitation-contraction (E-C) coupling has been reported in dystrophic muscle fibers from mdx mice and alterations in E-C coupling components may occur as a direct result of dystrophin deficiency. We hypothesized that muscle specific overexpression of IGF-I would reduce E-C uncoupling in mdx muscle. Mechanically-skinned EDL muscle fibers from mdx mice displayed a faster decline in depolarization-induced contractile responses (DICR), however, there were no differences in sarcoplasmic reticulum (SR)-mediated Ca²⁺ resequestration or in the properties of the contractile apparatus compared with non-dystrophic controls. The rate of DICR decline was restored to control levels in fibers from transgenic mdx mice that overexpressed IGF-I in skeletal muscle (mdx /IGF-I mice). Dystrophic muscles have a lower transcript level of a specific dihydropyridine receptor (DHPR) isoform and IGF-I-mediated changes in E-C coupling were associated with increased transcript levels of specific DHPR isoforms involved in Ca²⁺ regulation. Importantly, IGF-I overexpression also increased the sensitivity of the contractile apparatus to Ca²⁺. The results demonstrate that IGF-I can ameliorate fundamental aspects of E-C failure in dystrophic muscle fibers and that these effects are important for the improvements in cellular function induced by this growth factor.