Novel Role for Perinatal Myosin in Skeletal Muscle Development

Abstract

Previously, we identified an R674Q missense mutation in the MYH8 gene encoding the myosin heavy chain perinatal isoform (MyHCpn) in individuals with a rare Carney complex syndrome (CNC) variant. In CNC, familial cardiac myxomas occur in the setting of spotty skin pigmentation, extracardiac myxomas, endocrinopathy, and other neoplasms. Individuals with R674Q MYH8 mutations exhibit a typical CNC phenotype along with trismus pseudocamptodactyly limb contracture syndrome. To define the role of MyHCpn in mammalian development, we established a genetically engineered mouse line carrying the orthologous R674Q mutant MYH8 allele. Mice with ubiquitous knockin of R476Q Myh8 (Myh8R674Q/+;EIIa-Cre mice) die within minutes after birth due to respiratory failure. Gross examination of these mice at embryonic day (E)18.5 revealed smaller embryos with abdominal bulges. Upon histological examination of E18.5 Myh8R674Q/+;EIIa-Cre skeletal muscles, we observed fiber size variability, signs of apoptosis and increased muscle degeneration/regeneration. Electron microscopic images of striated muscles showed enlarged mitochondria, focal absence of myofibrils, loosely arrayed fiber bundles, and regional Z-line irregularities. We also observed the presence of nemaline rods indicative of nemaline myopathy. These findings suggest a novel and crucial role of MyHCpn in proper skeletal muscle development.