Abstrakt
Recent studies have indicated that ammonia plays an important role in the pathogenesis of muscle wasting in patients with liver cirrhosis and that branched-chain amino acids (BCAA; leucine, isoleucine, and valine) may act as a substrate for ammonia detoxification to glutamine (GLN). We determined the effects of enhanced availability the BCAA on ammonia detoxification to GLN and protein metabolism in two types of skeletal muscle under hyperammonemic conditions.
Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3+BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls.
L-[1-14C]leucine was used to estimate protein synthesis, and leucine oxidation and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and α-ketoglutarate (α-KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group.
Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL was observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in α-KG found in the NH3 group.
We conclude that (i) high levels of ammonia impair protein synthesis, activate BCAA oxidation, enhance GLN synthesis, and decrease glutamate and α-KG levels and (ii) that increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in α-KG.