CHRONIC REGULATION OF MITOCHONDRIAL CONTENT IN MUSCLE

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Summary of work: We are studying the chronic regulation of mitochondrial enzyme activity in muscle, with a view to understanding the weakness and decreased capacity for endurance training of skeletal muscle in old age. We are particularly concerned with mechanisms coordinating the expression of mitochondrial and nuclear genomes in the biogenesis of mitochondria. We have chosen to emphasize the enzyme cytochrome c oxidase, as it contains subunits encoded on each genome. Further, in its function of catalyzing the terminal step of electron transfer to oxygen, it exerts substantial control over oxidative phosphorylation. Last year we showed decreased enzymic activity of cytochrome oxidase in rat heart mitochondria as a function of aging and decreased rates of radiolabelled methionine incorporation into subunits encoded on mt-DNA. This year we have sought to establish the mechanism of this decrement. We have shown that the overall transcription of the mitochondrial genome, measured by labeled UTP incorporation into isolated rat heart mitochondria, is diminished with aging (24 month old male Wistar rat versus 6 month old). When individual transcripts are measured by Northern blots, message for COX 1 was significantly decreased, whereas message for COX II was not. As both are encoded on mt- DNA, which is transcribed to give a polycistronic message, other issues of message processing and/or stabilization may be involved. Expression of some of the nuclear-encoded subunits of cytochrome oxidase is also altered in aging. Thus, we find a decrease in COX V1c protein content. The presence of a binding sequence for the transcription factor NRF-1 on both the COX V1c gene and the gene for MTF-1, which is essential for replication and transcription of mt-DNA, suggests to us that many, or all, of these effects could be explained by a decrease with aging of NRF-1 levels. This is being studied.