ACTIVATION OF A NOVEL METABOLIC GENE REGULATORY PATHWAY BY CHRONIC STIMULATION OF SKELETAL-MUSCLE

To determine whether expression of a nuclear gene encoding a mitochond rial fatty acid oxidation enzyme is regulated in parallel with skeleta l muscle fiber-type-specific energy substrate preference, expression o f the gene encoding medium-chain acyl-CoA dehydrogenase (MCAD) was del ineated in canine latissimus dorsi muscle subjected to chronic motor n erve stimulation. In predominantly fast-twitch canine latissimus dorsi muscle, MCAD mRNA levels were regulated by chronic stimulation in a b iphasic pattern. During the 1st wk of stimulation, steady-state MCAD m RNA levels decreased to 50% of unstimulated levels. MCAD mRNA levels b egan to increase during the 3rd wk of stimulation to reach a level 3.0 -fold higher than levels in unstimulated contralateral control muscle by day 70. Immunodetectable MCAD protein levels paralleled MCAD mRNA l evels throughout the stimulation period. The temporal pattern and magn itude of MCAD mRNA accumulation in response to muscle stimulation was distinct from that of mRNAs encoding other enzymes known to be regulat ed by this stimulus, including glyceraldehyde phosphate dehydrogenase, citrate synthase, and sarcoplasmic reticulum Ca-ATPase, but parallele d the protein levels of the peroxisome proliferator-activated receptor (PPAR), an orphan member of the nuclear hormone receptor superfamily known to regulate genes encoding fatty acid oxidation enzymes in liver . The skeletal muscle expression pattern of PPAR was also similar to t hat of MCAD in unstimulated rat skeletal muscles with distinct fiber-t ype compositions. These results demonstrate that a nuclear gene encodi ng a mitochondrial beta-oxidation enzyme is dynamically regulated in a pattern that parallels skeletal muscle fiber-type-specific energy sub strate utilization and implicate an orphan nuclear receptor transcript ion factor as a candidate transducer of this response.