The effect of isoproterenol on amino acid concentrations in perfusate and skeletal muscle was studied during a 3-h perfusion of the isolated rat hemicorpus. The beta-adrenergic agonist inhibited the accumulation of alanine, threonine, phenylalanine, tyrosine, lysine, arginine, leucine, and valine and increased the loss of glutamate, aspartate, serine, and isoleucine from the pool of free amino acids in perfusate and muscle. The loss of glutamate was accompanied by a greater accumulation of glutamine. Changes in alanine levels showed the greatest response with a net accumulation of 98 mumol in the controls becoming a net loss of 54 mumol in the experimentals. These changes in amino acid levels were accounted for in part by a 20% decrease in protein degradation. Protein synthesis was not affected by isoproterenol. In addition to an effect on degradation, it appeared that isoproterenol affected amino acid levels by increasing alanine utilization and causing formation of glutamine instead of alanine. Other effects of the drug included increased rates of lactate production, muscle glycogen breakdown, and oxygen consumption, whereas no effects were observed on ATP and creatine phosphate levels. Pyruvate content of muscle was maintained at a higher level in the presence of the drug than in control perfusions.
The effects of thyroxine (T4) on protein turnover in skeletal muscle were studied using normal, thyroidectomized (thyrex), and hypophysectomized (hypox) rats. Thyrex rats had a depressed growth rate that was accompanied by 50% reductions in the level of RNA and the rate of protein synthesis in gastrocnemius muscle, as determined in the perfused hemicorpus. Protein synthetic efficiency (protein synthesis per unit RNA) was decreased by 18%. Daily treatment of thyrex rats with T4 at different dose levels for up to 16 days led to improved growth rates, elevated RNA concentrations, and increased protein synthesis rates. The primary effect of T4 was to increase the protein synthetic capacity of muscle. Protein degradation, determined in the perfused hemicorpus, and activity of a lysosomal protease, determined in unperfused muscle, were reduced in the thyrex condition. Treatment of thyrex rats with T4 increased protein degradative rates, but not protease activity. Hypox rats, which also exhibited depressed skeletal muscle protein synthesis, responded to T4 and combined T4 and growth hormone with marked improvements in protein synthesis.
The role of growth hormone in regulating protein turnover was examined in a perfused preparation of rat skeletal muscle. The perfused muscle maintained in vivo levels of ATP and creatine phosphate and exhibited constant rates of oxygen consumption and protein synthesis. Hypophysectomy reduced the rate of protein synthesis, the concentration of RNA, and the efficiency of protein synthesis in gastrocnemius muscle to 30, 46, and 66 percent of normal, respectively. In vivo treatment of hypophysectomized (hypox) rats with bovine growth hormone (250 microgram/day for 5 days) resulted in small increases in protein synthesis and RNA, whereas synthesis/RNA was returned to near normal. Elevation of ribosomal subunits in psoas muscle indicated an inhibition of peptide-chain initiation in hypox rats that was reversed by in vivo growth hormone treatment. Thus, hypox rats exhibited both a decreased capacity and a decreased efficiency of protein synthesis. Growth hormone replacement primarily increased efficiency of protein synthesis. The rate of protein degradation and the activity of cathepsin D in gastrocnemius muscle were decreased by hypophysectomy. Growth hormone treatment had no significant effect on degradation.
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