CL 316,243, a selective β3-adrenergic agonist, inhibits protein breakdown in rat skeletal muscle

Abstract

The in vitro effect of CL 316,243 (CL), a selective beta3-adrenoceptor agonist in the rate of overall proteolysis, the activity of proteolytic systems (lysosomal, Ca2+-dependent, ATP-dependent, and ATP-independent) and in the process of protein synthesis was investigated in rat skeletal muscles. The rate of overall proteolysis in soleus muscle from rats incubated with CL (10(-4) and 10(-5) M) or epinephrine (10(-5) M) was significantly decreased. In vitro rates of maximal activity of Ca2+-dependent proteolysis in soleus muscles were decreased by about 41% in the presence of 10(-5) M CL. No change was observed in the activities of the lysosomal, ATP-dependent or ATP-independent proteolytic systems. The anti-proteolytic effect of CL or epinephrine was partially prevented by 10(-5) M SR 59230A, a selective beta3-adrenoceptor antagonist. The increase of proteolysis induced by food deprivation in soleus was abolished by in vitro addition of 10(-5) M CL. No change in proteolysis was observed in extensor digitorum longus (EDL) muscles incubated with any concentration of the beta3-adrenoceptor agonist tested. Rates of protein synthesis were not affected by 10(-4) M CL neither in soleus nor EDL. The data suggest that a beta3-adrenoceptor-mediated inhibition of Ca2+-dependent proteolysis participates of the antiproteolytic effect of catecholamines in oxidative muscles.

The inhibitory role of sympathetic nervous system in the Ca2+-dependent proteolysis of skeletal muscle

“…In agreement with these results, the inhibitory in vitro effect of clenbuterol and CL-316,243 on the rate of overall proteolysis in isolated skeletal muscle from normal rats was shown to be associated with a reduction in the activity of the Ca 2+ -dependent proteolysis, an effect that was prevented by selective β 2 -and β 3 -antagonists (20,30).…”

“…We have previously shown that CL-316,243, a selective β 3 -adrenoceptor agonist, exerts an inhibitory action on proteolysis in rat-isolated soleus muscle. The inhibition of proteolysis induced by the addition of CL-316,243 to the incubation medium of soleus muscles from fed and fasted rats was completely prevented by SR-59230A, a selective β 3 -antagonist, but was not affected by selective β 1 -or β 2 -antagonists (30). Furthermore, we have demonstrated that the inhibitory effect of epinephrine on muscle protein degradation can also be prevented by SR-59230A, suggesting that this adrenergic effect may be mediated by β 3 -adrenoceptors (30).…”

“…The inhibition of proteolysis induced by the addition of CL-316,243 to the incubation medium of soleus muscles from fed and fasted rats was completely prevented by SR-59230A, a selective β 3 -antagonist, but was not affected by selective β 1 -or β 2 -antagonists (30). Furthermore, we have demonstrated that the inhibitory effect of epinephrine on muscle protein degradation can also be prevented by SR-59230A, suggesting that this adrenergic effect may be mediated by β 3 -adrenoceptors (30). It was interesting to note that, unlike soleus, the overall rates of proteolysis observed in fast-twitch muscles, such as EDL, from fed and fasted rats was not affected by CL-316,243.…”

“…It was interesting to note that, unlike soleus, the overall rates of proteolysis observed in fast-twitch muscles, such as EDL, from fed and fasted rats was not affected by CL-316,243. Taken together, these results suggest that epinephrine inhibits proteolysis by activating β 2 -and/or β 3 -adrenoceptors in oxidative muscles such as soleus (20,30). Further experiments are needed to determine the relative sensitivity of the different muscle fiber types to the β 3 -adrenergic agonist-mediated effects on proteolysis.…”

Controversial Issues Concerning Norepinephrine and Intensive Care Following Severe Traumatic Brain Injury

“…Sustained ATP and oxygen consumption of b-adrenergic-stimulated muscular Na + -K + -ATPase could contribute to muscle degradation. Norepinephrine-induced proteolysis [40] has been challenged by recent reports suggesting anabolic effects via stimulation of b 2 -and b 3 -adrenergic receptors in rats [41]. For the complex regulation of glucose metabolism, activation of a 2 -adrenergic receptors inhibits insulin secretion, thus elevating blood glucose levels due to attenuated uptake in myocytes and lipocytes while stimulation of a 1 -and b-adrenergic receptors increases pancreatic release of insulin which decreases blood glucose due to increased cellular uptake and intracellular degradation [42].…”