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dc.contributor.authorLu, Brian Der-Hua
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 61-02, Section: B, page: 6990.;Advisors: Leslie A. Leinwand.
dc.description.abstractVoluntary movements of vertebrates are created by the specialized tissue of skeletal muscle. To produce movement, chemical energy stored in ATP is converted into mechanical force by the Myosin Heavy Chain (MyHC) protein. Distinct genes encode the eight known members of the mammalian MyHC family. Two MyHC isoforms, embryonic and perinatal, constitute the majority of the MyHC in the embryo and may be specialized for initial sarcomere assembly. They are replaced by the adult isoforms IIb, IId/x, and IIa, listed in descending order of the twitch speed properties of fibers expressing them.;RNase protection assays (RPA) and in situ hybridization wore carried out to analyze the expression of 6 MyHC genes during mouse skeletal muscle development. Surprisingly, we detected expression of the three "adult" fast genes in the embryo with the MyHC IIb gene expressed first, at 14.5 dpc (days postcoitum) followed one day later by Ha and IId/x. Adult muscles were also analyzed by RPA for the expression of 6 MyHC genes. Our results provide evidence that the MyHC adult isoforms undergo dramatic shifts in expression during early neonatal life.;To study the role of individual MyHC genes in skeletal muscle development and function, two homozygous null mouse fines wore generated, one for the IId/x gone and another for the IIb gene by homologous recombination. These animals had low body mass, accompanied by decreases in mass of specific subsets of muscles. IId/x null mice had moderate reductions in mass of a small subset of individual muscles. The IIb null line exhibited a greater mass reduction in individual muscles, particularly limb muscles, resulting in some muscles being less than half the mass of wild-type. The MyHC gene expression profiles in muscles from these two lines of null mice revealed significant alterations in the expression of the remaining isoforms. In the IId/x null mice, the MyHC Ha gene compensated while in the IIb null mouse, it appeared that both the Ha and IId/x MyHC genes were compensating. These isoforms could not fully compensate for the loss of IId/x or IIb in their respective animals since both null animals have strong phenotypes. Evidence of degeneration is also seen in the affected muscles for the IIb null mouse. In situ hybridization and RPA were employed to examine the expression of the MyHC gene family during development in wild-type and null animals. There were reductions in the relative expression of the perinatal or embryonic isoforms in the developing null animals and in the IIb nulls after birth relative to wild-type. In situ hybridization analysis suggested that compensation by the IIa and IId/x genes in the IIb null animal starts during development, whereas compensation by the IIa gene in the IId null likely occurs after birth. This suggests some plasticity of the MyHC gene family in the maturation of muscle. The studies here represent the first detailed study of expression of the adult fast MyHC genes in development and their potential roles in skeletal muscle development and function.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.subjectAnimal Physiology.
dc.titleThe adult fast myosin heavy chains isoforms: Studies in development and consequences of gene disruption

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