Neural control of gene expression in skeletal muscle. Effects of chronic stimulation on lactate dehydrogenase isoenzymes and citrate synthase

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Abstract
1. The aim of this study was to investigate the effects of neural activity on the expression of fibre-type-specific patterns of metabolic enzymes at the levels of transcription and translation. 2. For this purpose, changes in tissue amounts of citrate synthase (CS) and the H- and M-subunits of lactate dehydrogenase (LDH) were followed in fast-twitch rabbit-muscles during low-frequency (10 Hz, 12 h/day) nerve stimulation. These stimulation-induced alterations were correlated with changes in tissue amounts of the total poly(A)+ (polyadenylated) RNA, poly(A)+ RNAs specifically translatable in vitro, yield of total ribosomes and distributions of monosomes and polysomes. The tissue contents of poly(A)+ RNAs translatable in vitro coding for CS and H- and M-LDH were quantified by immunoprecipitation of their translation products. 3. Increases in total ribosome yields occurred after 4 days'' stimulation, reaching a maximum between 14 and 21 days. Stimulation for only 1-2 days greatly increased the amount of monosomes. An increase in polysomes occurred before that in total ribosomes, suggesting that monosomes were integrated into polysomes. 4. Total poly(A)+ RNA significantly increased in muscles stimulated for more than 6 days. A maximum increase of 2.5-fold was attained after 14-21 days. 5. Chronic stimulation progressively induced the appearance of LDH isoenzymes containing the H-subunit, with a predominance of LDH-3. This shift corresponded to a slow decay of the M-subunit and a 2-fold steep increase in the H-subunit. These changes correlated with those of the respective poly(A)+ RNAs translatable in vitro, thus indicating that the re-arrangement of the LDH isoenzyme pattern is mainly due to qualitatively and quantitatively altered transcription. 6. The increase in CS was biphasic and consisted of a moderate rise during the first 4 days of stimulation and a steep rise thereafter. The latter coincided with a steep increase in poly(A)+ RNA translatable in vitro coding for CS. In view of the early increase in translational capacity, it was concluded that the initial rise in CS resulted from selective post-transcriptional control and enhanced translation in vivo of existing mRNA, whereas its steep increase was due to enhanced transcription. 7. These results indicate that the neurally regulated expression of phenotype-specific properties in muscle includes control of both transcription and translation.