Muscle protein turnover and glucose uptake in acutely uremic rats. Effects of insulin and the duration of renal insufficiency.

Abstract

A B S T R A C T Acute renal failure (ARF) in rats is associated with increased amino acid release from peripheral tissues and insulin resistance. To study whether abnormal protein and carbohydrate metabolism are linked in ARF, the effects of insulin on net muscle protein degradation (T) and on glucose uptake were measured in the perfused hindquarters of paired ARF and sham-operated (SO) rats. The basal rate of T increased 40% after 24 and 98% after 48 h of ARF. Insulin was less effective in decreasing T in ARF (-79% SO vs. -22% ARF 24 h and -64% SO vs. -23% ARF 48 h; P < 0.01). Protein synthesis (PS) and protein degradation (PD) were measured independently in incubated epitrochlearis muscles; the increase in T after 24 h of ARF was due specifically to increased PD, while PS was unchanged. At this stage, insulin was less effective in decreasing PD in ARF (-10% ARF vs. -23% SO; P < 0.02), although PS responded normally. After 48 h of ARF, the further increment in T was caused by the additional appearance of depressed basal and insulin-stimulated PS. This was confirmed in the perfused hindquarter (26±3 ARF vs. 38±3 SO, basal; 54±5 ARF vs. 73±7 SO, insulin-stimulated, nmol phenylalanine/g per h; P < 0.05).Although basal glucose uptake by hindquarters of ARF and SO rats was comparable, insulin-stimulated glucose uptake was 33% less at 24 and 44% less after 48 h of ARF. After 48 h of ARF, lactate and alanine release were increased and net glycogen synthesis in muscle was depressed. These abnormalities were even more apparent in the presence of insulin. Inefficient glucose utilization, estimated as the ratio of lactate Address reprint requests to Dr. Mitch.

Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.

“…Previously, we found that the rate of muscle protein degradation was positively correlated with the ratio ofglycolysis (or lactate release) to glucose uptake in muscles of normal rats and rats responding to catabolic conditions (9,25,26). DCA did not significantly change the rate of muscle protein degradation even though it sharply reduced this ratio.…”

The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway.

“…Unfortunately, the amount of muscle and the methods required to measure these responses in the same muscle prevented us from arriving at an easy answer. However, we predict that these changes occur in most types of skeletal muscle for the following reasons: (a) The epitrochlearis muscle we used to measure protein degradation and the gastrocnemius used for RNA analyses contain both red and white types of muscle fiber (33,39), and protein degradation in mixed-fiber muscles responds similarly to fasting and acute uremia (28,40); (b) we found that mRNAs of ubiquitin and proteasome subunits in the predominantly white-fiber EDL and mixed-fiber gastrocnemius muscles increase in response to acidemia and glucocorticoids (41); and (c) in response to another catabolic condition, starvation, protein degradation and mRNAs of components of the ubiquitinproteasome system are increased in EDL and in the red-fiber soleus muscle of rats (30,42).…”

Systemic response to thermal injury in rats. Accelerated protein degradation and altered glucose utilization in muscle.

“…Protein synthesis was calculated by measuring the rate of incorporation of U-'4C-phenylalanine into muscle protein and dividing it by the specific radioactivity (0.1 mCi/mmol) of phenylalanine in the media (16,17). PD was determined in separate experiments by measuring the rate of release of tyrosine into the media in the presence of 0.5 mM cycloheximide.…”

“…Glucose was measured using a Beckman Glucose II analyzer (Beckman Instruments, Inc., Palo Alto, CA), which we have found to have a coefficient of variation of 1.5% with glucose measured enzymatically (17). Urea nitrogen appearance was calculated as the algebraic sum of urea nitrogen excretion, and the change in the urea nitrogen pool which was measured as the product of plasma urea nitrogen and the volume of distribution of '4C-urea (35).…”