Little is known of the events that initiate the adaptive response of skeletal muscle to a sustained change in use. This study was designed to distinguish between the role of the electrical activity pattern and that of the resulting contractile force in driving different aspects of the response. A better understanding of these issues would lead to improved clinical protocols for functional electrical stimulation. Rabbit limb muscles were stimulated continuously for 12 weeks either at 2.5 Hz or with an equivalent optimized pattern producing peak forces three-fold higher. The two patterns induced similar changes in shortening velocity, myosin isoforms, and fatigue resistance. They had markedly different effects on twitch dynamics and summation ("doublet effect"). This pointed to differences in activation that were not, however, attributable to sarcoplasmic reticulum Ca(2+) transport ATPase activity. The optimized pattern maintained muscle bulk more effectively. We conclude that changes in myosin isoform composition and fatigue resistance are driven by aggregate impulse activity. Changes in Ca(2+) transport and muscle bulk show a distinct pattern dependence.