Carbohydrate metabolism and the beta-adrenergic system in disuse muscle atrophy.

Abstract

Hindlimb un weighting by tail-cast suspension markedly alters the carbohydrate metabolism of rat soleus muscle. Due to reduced contractile activity, muscle glycogen concentrations increase dramatically. When normal weight-bearing function is restored (reloading), a triphasic response characterizes the return of glycogen to control levels. Between 15 min and 2 h of reloading, muscle glycogen concentrations decrease as a consequence of increased fractional activity of glycogen phosphorylase. From 2 to 4 h, phosphorylase activity declined and an elevated activity of glycogen synthase led to increased glycogen levels. Further increases of glycogen up to 24 h did not correlate with enzyme activities, thereby suggesting a transient uncoupling of the inverse relationship between glycogen concentrations and synthase activity. Between 24 and 72 h of reloading, glycogen decreased to control values, possibly initiated by high phosphorylase activity at 24 h. Further studies concerning the B-adrenergic response of carbohydrate metabolism showed that isoproterenol inhibition of glucose uptake and the mechanism by which isoproterenol inhibits skeletal muscle glucose uptake were similar in unweighted and weight-bearing soleus muscle. In contrast, isoproterenol effects on glycogen metabolism were increased in unweighted, but not denervated, soleus. Increased response of cAMP accumulation to isoproterenol but not to forskolin, which directly activates adenylate cyclase, suggested a receptor-mediated alteration in B-adrenergic response. Greater Badrenergic binding capacity per milligram muscle in unweighted soleus confirmed this hypothesis. Since the number of B-receptors in the muscle did not change following unweighting, this suggests that increased receptor concentration in unweighted muscle is due to a preferential loss of structural proteins and not receptor up-regulation. Conversely, denervation did not alter the number of receptors per milligram muscle, but reduced the total number of receptors in the muscle. These findings support a parallel loss of receptor and non-receptor protein during denervation. Since membrane receptors are degraded in lysosomes, contrasting B-adrenergic responses and binding capacities provided a novel means for showing marked differences in lysosomal proteolysis between unweighted and denervated muscle. Results from these studies indicate that while both unweighting and denervation induce muscle atrophy, mechanisms of proteolysis and hormonal responses in these two models of reduced use are markedly different.