Rescue of Cardiac α -Actin-Deficient Mice by Enteric Smooth Muscle γ -Actin

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (9), p.4406-4411
• Main Authors: Kumar, A., Crawford, K., Close, L., Madison, M., Lorenz, J., Doetschman, T., Pawlowski, S., Duffy, J., Neumann, J., Robbins, J., Boivin, G. P., O'Toole, B. A., Lessard, J. L.
• Format: Article
• Language: English
• Subjects: Actins; Actins - genetics; Amino acids; Animals; Biological Sciences; Cellular biology; Genes, Lethal; Genetic Complementation Test; Genotypes; Heart; Heart - physiology; Heart Function Tests; Heterozygote; Homozygote; Intestine, Small - chemistry; Messenger RNA; Mice; Mice, Mutant Strains; Muscle, Smooth - chemistry; Muscles; Myocardial Contraction; Myocardium; Myocardium - pathology; Protein isoforms; Proteins; Recombinant Proteins - biosynthesis; Rodents; Smooth muscle; Tissue Distribution; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.9.4406

The muscle actins in higher vetebrates display highly conserved amino acid sequences, yet they show distinct expression patterns. Thus, cardiac α -actin, skeletal α -actin, vascular smooth muscle α -actin, and enteric smooth muscle γ -actin comprise the major actins in their respective tissues. To assess the functional and developmental significance of cardiac α -actin, the murine (129/SvJ) cardiac α -actin gene was disrupted by homologous recombination. The majority (≈ 56%) of the mice lacking cardiac α -actin do not survive to term, and the remainder generally die within 2 weeks of birth. Increased expression of vascular smooth muscle and skeletal α -actins is observed in the hearts of newborn homozygous mutants and also heterozygotes but apparently is insufficient to maintain myofibrillar integrity in the homozygous mutants. Mice lacking cardiac α -actin can be rescued to adulthood by the ectopic expression of enteric smooth muscle γ -actin using the cardiac α -myosin heavy chain promoter. However, the hearts of such rescued cardiac α -actin-deficient mice are extremely hypodynamic, considerably enlarged, and hypertrophied. Furthermore, the transgenically expressed enteric smooth muscle γ -actin reduces cardiac contractility in wild-type and heterozygous mice. These results demonstrate that alterations in actin composition in the fetal and adult heart are associated with severe structural and functional perturbations.