Ablation of the murine α myosin heavy chain gene leads to dosage effects and functional deficits in the heart

The α-myosin heavy chain (α-MyHC) is the major contractile protein expressed in the myocardium of adult mice. We have produced mice carrying a null mutation of α-MyHC by homologous recombination in murine ES cells. Homozygous null animals die between 11 and 12 d in utero of gross heart defects, while α-MyHC(+/-) heterozygotes survive and appear externally normal. The presence of a single functional α-MyHC⁺ allele in heterozygous animals results in reduced levels of the transcript and protein as well as fibrosis and alterations in sarcomeric structure. Examination of heart function using a working heart preparation revealed severe impairment of both contractility and relaxation in a subset of the α-MyHC(+/-) animals. Thus, two α-MyHC⁺ alleles are necessary for normal cardiac development, and hemizygosity for the normal allele can result in altered cardiac function.