PROXIMAL SEQUENCES OF THE ALDOLASE-A FAST MUSCLE-SPECIFIC PROMOTER DIRECT NERVE-DEPENDENT AND ACTIVITY-DEPENDENT EXPRESSION IN TRANSGENIC MICE

Muscle activity is known to modulate the muscle fiber phenotype, Chang es in muscle activity (normal or experimentally induced) lead to modif ications of the expression status of several muscle-specific genes. Ho wever, the transcription regulatory elements involved in the adaptativ e response are mainly unknown. The aldolase A muscle specific promoter , pM, is expressed in adult fast twitch muscle with a preferential exp ression in fast glycolytic-2B fibers. Its activity is induced during p ostnatal muscle maturation, suggesting a role of nerve and/or muscle a ctivity. Indeed, denervation of gastrocnemius in newborn mice prevente d the activation of the promoter in this muscle, despite the nerve-ind ependent formation of 2B fibers. Although the nerve was necessary for pM onset during development, denervating the gastrocnemius in adults h ad only mild effects on pM activity. By contrast, a transgene includin g the pM proximal regulatory sequences that are sufficient to reproduc e the 2B fiber-specific expression of the endogenous promoter was show n to be highly sensitive to both neonatal and adult denervation, Trans genes containing muscle-specific pM proximal promoter elements were us ed to delineate the regulatory elements involved in this response to i nnervation and changes in the contractile activity pattern. Nerve- and activity-dependent elements could be localized in the 130-base pair-l ong proximal promoter region of the human aldolase A gene.