Alcoholic cardiomyopathy and skeletal myopathy have a serious impact on longevity and quality of life in individuals afflicted with chronic alcoholism. These myopathies are associated with alterations in contractility and in fiber composition, similar findings to those observed in thyroid hormone induced myopathies. Vitamin A deficiency is a frequent finding in chronic alcoholism and ethanol inhibits the intracellular synthesis of trans- and 9-cis retinoic acid (RA) from Vitamin A. These Vitamin A metabolites and their family of nuclear receptors interact as cofactors with thyroid hormone to regulate transcription of myocyte-specific genes important for contractility. We propose that chronic ethanol ingestion impairs cardiac and skeletal muscle function by altering Vitamin A promoted expression of specific myocyte contractile genes. We intend to study the molecular mechanisms by which ethanol modulates expression of Vitamin A responsive genes in neonatal rat cardiomyocytes and L6 skeletal myotubes. The initial studies will investigate the ability of ethanol to modulate the effects of Vitamin A (retinol) on the mRNA content of the cardiac and skeletal muscle specific alpha actin and sarcoplasmic reticulum genes. The effects of ethanol on promoter activity of these Vitamin A responsive genes will be measured using transient transfection assays to ascertain that transcription per se is altered. To examine the mechanisms by which ethanol may impair Vitamin A action, we will determine whether supplementation of the active metabolites of Vitamin A, RA and 9-cis RA will overcome ethanol inhibition of promoter activity. The completion of these studies should provide an important basis for understanding the pathophysiology of ethanol-induced cardiac and skeletal myopathy. These studies will lead to further investigation of the role of ethanol on Vitamin A metabolism including regulation of DNA binding of the Vitamin A receptor families RAR and RXR. Additional studies of the effects of ethanol on the regulation of intracellular transport of Vitamin A metabolites will also further our understanding the effects of ethanol on Vitamin A metabolism. These studies will serve as the basis for clinical studies of the role of supplementation of Vitamin A metabolites in the treatment of ethanol-induced cardiac and skeletal myopathies.
