Inactivation of myosin heavy chain genes in the mouse: Diverse and unexpected phenotypes

Myosin heavy chain (MyHC) is a critical component of the cellular contracti le apparatus. The mammalian genome contains two nonmuscle, two smooth muscl e, and eight striated muscle isoforms of MyHC. Within each class of genes, there is extremely high sequence homology among different MyHC isoforms, ra ising the question of whether these isoforms are functionally redundant or whether they perform unique roles in cell function. Recently, strains of mi ce null for four different MyHC isoforms have been generated. Mice null far the nonmuscle II-B isoform experience significant prenatal lethality and s urviving animals have several cardiac abnormalities [Tullio et al. (1997) P roc Natl Acad Sci USA 94:12407-12412]. Mice homozygous null for alpha cardi ac MyHC are embryonic lethal, while heterozygous mice are viable but also h ave numerous cardiac defects [Jones et al. (1996) J Clin Invest 98:1906-191 7]. Mice null for IIb or IId adult skeletal MyHC are viable but have skelet al muscle abnormalities compared to wild type mice, despite compensation of a neighboring MyHC gene [Acakpo-Satchivi et al. (1997) J Cell Biol 139:121 9-1229]. Both IIb and IId null mice show significant decreases in body mass . Mean muscle mass is also significantly decreased in both null strains but the extent and the pattern of affected muscles differs between the two str ains. Both strains show evidence of skeletal muscle pathology but again the pattern and extent differ between the two strains. Finally, both adult ske letal strains demonstrate distinct impairments in contractile function when compared to wild type. Together these observations support the hypothesis that the different isoforms of MyHC are functionally unique and cannot subs titute for one another. (C) 2000 Wiley-Liss, Inc.