A B S T R A C T Muscle glycogen stores are depleted during exercise and are rapidly repleted during the recovery period. To investigate the mechanism for this phenomenon, untrained male rats were run for 45 min on a motor-driven treadmill and the ability of their muscles to utilize glucose was then assessed during perfusion of their isolated hindquarters. Glucose utilization by the hindquarter was the same in exercised and control rats perfused in the absence of added insulin; however, when insulin (30-40,000 MU/ml) was added to the perfusate, glucose utilization was greater after exercise. Prior exercise lowered both, the concentration of insulin that half-maximally stimulated glucose utilization (exercise, 150 ,U/ml; control, 480 ,gU/ml) and modestly increased its maximum effect.The increase in insulin sensitivity persisted for 4 h following exercise, but was not present after 24 h. The rate-limiting step in glucose utilization enhanced by prior exercise appeared to be glucose transport across the cell membrane, as in neither control nor exercised rats did free glucose accumulate in the muscle cell.Following exercise, the ability of insulin to stimulate the release of lactate into the perfusate was unaltered; however its ability to stimulate the incorporation of ['4C]glucose into glycogen in certain muscles was enhanced. Thus at a concentration of 75 AU/ml insulin stimulated glycogen synthesis eightfold more in the fast-twitch red fibers of the red gastrocnemius than it did in the same muscle of nonexercised rats. In contrast, insulin only minimally increased glycogen synthesis in the fast-twitch white fibers of the gastrocnemius, which were not glycogen-depleted. The uptake of 2-deoxyglucose by these muscles followed a similar pattern suggesting that glucose transport was also differentially enhanced. Prior exercise did not enhance
In previous studies, interleukin-1 (IL-1) or tumor necrosis factor (TNF) have been demonstrated to augment skeletal muscle protein breakdown in a manner similar to that induced by bacterial endotoxin. This response to IL-1 or TNF was elicited only after they were administered to animals for various periods, as their addition in vitro to incubated muscles from normal untreated rats was without effect. This suggested that IL-1 and TNF may augment muscle proteolysis in an indirect fashion. Serum levels of IL-1, TNF as well as interleukin-6 (IL-6) are all elevated during infection induced by bacterial endotoxin. Both IL-1 and TNF can induce the synthesis of IL-6 by a variety of cells. Because of this, in the present report, the ability of IL-6 to stimulate skeletal muscle protein breakdown was examined. Muscle protein breakdown was evaluated by measuring the release of both tyrosine and 3-methylhistidine by incubated muscles. Pretreatment of rats with IL-6 for 6 hr induced fever and increased the release of both tyrosine and 3-methylhistidine by the extensor digitorum longus muscle. However, IL-6 did not augment muscle proteolysis when muscles from normal untreated rats were incubated in the presence of the cytokine. The data suggest that the acute treatment of animals with IL-6 can augment muscle proteolysis. Whether this response is due to a direct effect of IL-6 on the myocyte or whether it is due to the production of other mediators remains unclear.
The metabolic response to infection includes loss of lean tissue and increased nitrogen excretion. The loss of muscle tissue during infection results in large part from accelerated skeletal muscle protein breakdown. Recent studies suggest that macrophage-derived products secreted during infection may signal increased muscle proteolysis. To test this, in the present report the ability of interleukin (IL-1) and tumor necrosis factor (TNF) to enhance muscle proteolysis was examined. Young rats were injected intravenously with either recombinant human IL-1 or TNF. For comparison some rats were injected with bacterial endotoxin. Eight hours after each treatment, the extensor digitorum longus muscles were isolated and incubated in vitro to assess muscle proteolysis by measuring tyrosine and 3-methyl-L-histidine release by the incubated muscles. Treatment of rats with either IL-1, TNF, or endotoxin all induced fever, increased serum lactate, and reduced serum zinc levels. Despite similar metabolic changes, muscle proteolysis responded differently. As expected, endotoxin treatment enhanced muscle protein breakdown, whereas IL-1 treatment was without effect. On the other hand, TNF was effective in accelerating muscle protein breakdown. TNF addition in vitro failed to enhance muscle proteolysis by incubated muscles, suggesting that its effects may be mediated in an indirect manner; however, a direct mode of action cannot yet be ruled out. Overall, the data indicate that the acute administration of TNF can signal increased muscle proteolysis similar to that observed during infection.
Studies in the rat suggest that after voluntary exercise there are two phases of glycogen repletion in skeletal muscle (preceding study). In phase I glucose utilization and glycogen synthesis are enhanced both in the presence and absence of insulin, whereas in phase II only the increase in the presence of insulin is found. To determine whether these alterations and in particular those mediated by insulin are due to local or systemic factors, one hindlimb of an anesthetized rat was electrically stimulated, and both hindlimbs were perfused immediately thereafter. Glucose and glycogen metabolism in the stimulated leg closely mimicked that observed previously after voluntary exercise on a treadmill. With no insulin added to the perfusate, glucose incorporation into glycogen was markedly enhanced in muscles that were glycogen depleted as were the uptake of 2-deoxyglucose and 3-O-methylglucose. Likewise, the stimulation of these processes by insulin was enhanced and continued to be so 2 h later when the muscles of the stimulated leg had substantially repleted their glycogen stores. The results suggest that the increases in insulin-mediated glucose utilization and glycogen synthesis in muscle after exercise are modulated by local contraction-induced factors.
To examine the role of lysosomes in the degradation of skeletal-muscle myofibrillar proteins, we measured the release of N tau-methylhistidine from perfused muscle of starved and fed rats in the presence or absence of agents that inhibit lysosomal proteinase activity. After 1 day of starvation, the release of N tau-methylhistidine by perfused muscle of 4-, 8- and 24-week-old rats increased by 322, 159 and 134% respectively. On the other hand, total protein breakdown, assessed by tyrosine release, increased by 62, 20 and 20% respectively. Inhibitors of lysosomal proteinases as well as high concentrations of insulin or amino acids failed to diminish the release of N tau-methylhistidine by perfused muscle of starved and fed rats, despite a 25-35% inhibition of total protein breakdown. The data strongly suggest that the complete breakdown of myofibrillar proteins occurs via a non-lysosomal pathway. They also suggest that total proteolysis, which primarily reflects non-myofibrillar protein breakdown, occurs at least in part within lysosomes.
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