J Biol Chem, Vol. 273, Issue 24, 14975-14981, June 12, 1998

Proximal Sequences of the Aldolase A Fast Muscle-specific Promoter Direct Nerve- and Activity-dependent Expression in Transgenic Mice

From the INSERM U129, Institut Cochin de Génétique Moléculaire, Université René Descartes Paris V, 24 rue du Faubourg Saint Jacques, 75014 Paris, France, the ^§ Laboratoire de Neurobiologie, URA-CNRS 1448, Université René Descartes Paris V, 45 rue des Saints-Pères, 75006 Paris, France, and the ^¶ URA CNRS 1283, Centre Hospitalo-Universitaire Saint Antoine, 27 rue de Chaligny, 75012 Paris, France

Muscle activity is known to modulate the muscle fiber phenotype. Changes in muscle activity (normal or experimentally induced) lead to modifications of the expression status of several muscle-specific genes. However, the transcription regulatory elements involved in the adaptative response are mainly unknown. The aldolase A muscle-specific promoter, pM, is expressed in adult fast twitch muscle with a preferential expression in fast glycolytic-2B fibers. Its activity is induced during postnatal muscle maturation, suggesting a role of nerve and/or muscle activity. Indeed, denervation of gastrocnemius in newborn mice prevented the activation of the promoter in this muscle, despite the nerve-independent formation of 2B fibers. Although the nerve was necessary for pM onset during development, denervating the gastrocnemius in adults had only mild effects on pM activity. By contrast, a transgene including the pM proximal regulatory sequences that are sufficient to reproduce the 2B fiber-specific expression of the endogenous promoter was shown to be highly sensitive to both neonatal and adult denervation. Transgenes containing muscle-specific pM proximal promoter elements were used to delineate the regulatory elements involved in this response to innervation and changes in the contractile activity pattern. Nerve- and activity-dependent elements could be localized in the 130-base pair-long proximal promoter region of the human aldolase A gene.