Acetyl-CoA carboxylase beta expression mediated by MyoD and muscle regulatory factor 4 is differentially affected by retinoic acid receptor and retinoid X receptor.

ABSTRACT

Mammals have two major isoforms of acetyl-CoA carboxyase (ACC). The 275 kDa beta-form (ACCbeta) is predominantly in heart and skeletal muscle while the 265 kDa alpha-form (ACCalpha) is the major isoform in lipogenic tissues such as liver and adipose tissue. ACCbeta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine palmitoyl-CoA transferase-1 (CPT-1), which is a rate-limiting enzyme of fatty acid oxidation in mitochondria. Previously, it was reported that MyoD and other muscle regulating factors (MRFs) up-regulate the expression of ACCbeta by interactions between these factors and several cis-elements of ACCbeta promoter. We described here that ACCbeta expression mediated by MRFs is regulated by retinoic acids. Endogenous expression of ACCbeta in differentiated H9C2 myotube was significantly increased by retinoic acid treatment. However, on transient transfection assay in H9C2 myoblast, ACCbeta promoter activity was suppressed by RXRalpha and more severely by RARalpha. These effects on ACCbeta expression in myoblasts and myotubes by RXRalpha and RARalpha seem to be mediated by their interactions with MRFs because no consensus sequence for RXRalpha and RARalpha has been found in ACCbeta promoter and retinoic acid receptors did not affect this promoter activities by itself. In transient transfection in NIH3T3 fibroblast, the activation of ACCbeta promoter by MyoD, main MRF in myoblast, was significantly suppressed by RARalpha and to a less extent by RXRalpha while the RXRalpha drastically augmented the activation by MRF4, major MRF in myotube. These results explained that retinoic acids differentially affected the action of MRFs according to their types and RXRalpha specially elevates the expression of muscle specific genes by stimulating the action of MRF4.