Defining alpha-skeletal and alpha-cardiac actin expression in human heart and skeletal muscle explains the absence of cardiac involvement in ACTA1 nemaline myopathy.

Mutations in alpha-skeletal actin (ACTA1) underlie several congenital muscle disorders including nemaline myopathy (NM). Almost all ACTA1-NM patients have normal cardiac function, and, even lethally affected congenital NM patients exhibit an unremarkable gestation with decreased foetal movement just prior to birth. Although alpha-skeletal actin is thought to be the predominant sarcomeric actin in human heart (Boheler KR, Carrier L, de la Bastie D, et al. Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts. J Clin Invest 1991;88:323-30 ), ACTA1-NM patients almost never exhibit a cardiac phenotype. In this study, we define the relative expression of skeletal and cardiac actin proteins in human heart and skeletal muscle. We show that alpha-cardiac actin is the predominant sarcomeric isoform in human donor hearts and in early foetal skeletal muscle development. Skeletal actin is the predominant isoform from 25 to 27 weeks gestation and is the exclusive isoform expressed in muscle from infancy through to adulthood. These findings are consistent with clinical observations of NM patients and assist us to better understand the pathogenesis of inherited myopathies and cardiomyopathies with mutations in actin.