During the development of skeletal muscle, myoblasts withdraw from the cell cycle and differentiate into myotubes. The insulin-like growth factors IGF-I and IGF-II, through their cognate tyrosine kinase receptor (IGF-I receptor), are known to play a role in this process. After withdrawal of myoblasts from the cell cycle, IGF-I promotes muscle differentiation by inducing the expression or activity of myogenic regulatory factors (MyoD, myogenin) and effectors (p21). However, little is known about the intracellular mechanisms by which the IGF-I system regulates these factors during the process of myogenesis. Here we show that MKR mice, which express a dominant negative IGF-I receptor specifically in skeletal muscle, have marked muscle hypoplasia from birth to 3 weeks of age. This hypoplasia occurs concomitantly with a decrease in ERK immunoreactivity levels and decreases in MyoD and myogenin expression. BrdU immunocytochemistry showed a compensatory hyperplasia as MKR mice grew to adulthood. Interestingly, hyperplasia occurred concomitantly with an increase in p38, MyoD, myogenin, and p21 immunoreactivity levels, as well as a decrease in Twist levels. These findings suggest that regulation of these cellular elements by IGF-I may play a role in the development and differentiation of skeletal muscle in vivo.