The long-term goals of this research are to define the biochemical mechanisms regulating the expression of genes encoding proteins required for energy production in mammalian striated muscle, and to apply this mechanistic knowledge to the development of novel approaches to the therapy or prevention of cardiovascular diseases.
The specific aims of the present proposal are to distinguish transcriptional from posttranscriptional mechanisms of gene regulation, to clarify the basis for coordinated regulation of nuclear and mitochondrial genes, and to examine the importance of specific molecular signals governing gene regulation during mitochondrial proliferation or regression induced in response to changing contractile activity in cardiac and skeletal muscle. Adult rabbits will be subjected either to indirect electrical stimulation of skeletal muscle or to aortic banding to promote pressure overload hypertrophy of cardiac muscle for periods of time varying between two days and ten weeks. These stimuli promote major increases in mitochondrial mass and enzymatic capacity as an initial response to increased contractile work in both tissues, but the late responses differ in skeletal muscle and in heart. The cellular concentrations and molecular size of specific mRNA transcripts of genes at encode selected cytoplasmic and mitochondrial proteins will be quantitated in muscle samples by nucleic acid hybridization techniques using recombinant DNA probes, or by in vitro translation studies using specific antibodies, in conjunction with studies of mitochondrial morphology and enzymatic capacity. In addition, studies of the regulation of mitochondrial mucleic acid synthesis in mitochondria isolated from striated muscle will be pursued. Finally, the effects of several pharmacologic interventions that may influence hypothetical molecular signals governing regulation of expression of genes encoding proteins involved in energy production in skeletal and cardiac muscle will be investigated.
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