Disuse of muscle leads to atrophy of the fibers. This atrophy is correlated with reduced transcription. We found that when muscle was denervated or paralyzed with a nerve impulse block, the mRNA for Id-1, a negative regulator of transcription, was increased 2- to 7-fold. To test the effect of high Id-1 levels in active muscles, we made transgenic mice in which Id-1 was overexpressed under control of regulatory elements which confer tissue- and fiber-type-specific expression in differentiated muscle cells. Fiber types with high transgene expression were atrophic compared to those in wild-type litter mates. In contrast, fiber types with low transgene expression displayed hypertrophy, presumably caused by an overload due to reduced strength in atrophic synergistic fibers. Apart from the selective effects on fiber caliber, the muscle tissue showed no signs of pathology, and apart from a characteristic slightly lower body weight, the transgenic animals looked and behaved normally. We suggest that in the mature muscle, Id-1 may be involved in regulating muscle fiber size at the transcriptional level during disuse.