Changes in human myosin heavy chain gene expression in development and disease

Abstract

The muscle protein myosin is a major component of the contractile apparatus and is responsible for force transduction through the hydrolysis of ATP. Striated muscle MHC is encoded by a highly conserved multigene family whose members show developmental and tissue specific regulation. Generation of gene-specific probes for each of these isoforms has allowed the examination of changes in MHC gene expression during development and in disease states.;The isolation and characterization of a full-length cDNA clone encoding the human perinatal MHC isoform is reported here. Northern blot and RNAse protection studies were used to determine that the perinatal MHC gene is expressed predominantly in fetal skeletal tissue, but continues to be expressed at low levels in adult skeletal tissue.;The pattern of MHC gene expression in clonal cultures of fetal skeletal myoblasts was examined as a function of time after fusion. Unlike the regulated transitions which occur in vivo, we have determined that, under the conditions used, the myotubes appear to be expressing both fetal and adult isoforms immediately post fusion.;Changes in MHC gene expression in pathologically overloaded human hearts were examined using probes for {dollar}\alpha{dollar} and {dollar}\beta{dollar} MHC and V-MLC1 mRNAs. These studies have shown an increase in {dollar}\beta{dollar} MHC expression and a concomitant decrease in {dollar}\alpha{dollar} MHC expression in the left atrium and both ventricles of these hearts. We can correlate the extent of change in isoform expression with the degree of overload, showing that the heart is undergoing an adaptive transition.;Using in situ hybridization we have examined the presence of mRNAs for five skeletal MHC isoforms on a fiber by fiber basis in muscle from normal and Duchenne muscular dystrophy patients. We observed expression of the embryonic and perinatal isoforms in normal adult skeletal tissue and have characterized the expression pattern of a slow and two fast MHC isoforms in adult fibers. We noted a small increase in the number of fibers expressing the embryonic and perinatal isoforms in Duchenne tissue. We believe that this aberrant expression is due to the regeneration of fibers which occurs during the early stages of this disease.