Muscle wasting is a significant clinical problem and associated with multiple conditions including cancer cachexia, AIDS, sepsis, and severe injury. It is known that an absolute increase in protein degradation rates is probably the most important mechanism of muscle wasting. It is obvious, then, that methods to prevent myofibrillar protein degradation will have significant clinical implications in multiple groups of patients and will markedly promote the healthy growth of livestock and poultry.

Amino acids, especially leucine, have been regarded as a potent agent to inhibit protein degradation. However, there has been growing recognition that leucine metabolites β-hydroxy-β-methyl-butyrate (HMB) also exert important roles in inhibiting protein degradation. It is on this basis that much attention has been given to HMB.

Using a starvation model, a team of researchers from China Agricultural University and the Institute of Subtropical Agriculture (ISA) of the Chinese Academy of Sciences found that HMB (50 μM) is more superior than leucine (0.5 mM) in effectively suppressing protein degradation of C2C12 myotubes.

However, it remains unknown whether HMB mediates the inhibitory effects of leucine on protein degradation, and whether the protective effect of HMB is still more effective than that of leucine when its treatment concentration is fay beyond physiological limits.

Recently, the researchers conducted another study to compare and contrast the effects of HMB and different dosages of leucine on protein degradation in a starvation model and unravel the underlying mechanisms of HMB action on protein degradation.

They found that the beneficial effects of Leu on protein degradation and the oxygen consumption rate (OCR) of cells were observed at low levels (0.5 mM) rather than at high levels (10 mM). However, these effects were inferior to those of HMB. Moreover, HMB was able to increase/decrease the proportion of MyHC I/MyHC IIb protein expression, respectively. These results suggest that HMB seems to be an active metabolite of Leu to suppress muscle protein degradation in a starvation model.

Based on these observations, the authors hypothesized that in catabolic states, the transamination of leucine to HMB in muscle cells is the limiting step to obtain a complete response on protein degradation.
To test this possibility, they transfected C2C12 myotubes with a plasmid pKICD to over-express this key enzyme for the conversion of leucine to HMB, since KICD is mainly expressed in the liver.

In these KICD-transfected cells, leucine was approximately as effective as HMB in inhibiting protein degradation and increasing the OCR as well as MyHC I protein expression of cells, and these effects of leucine were reverted to a normal state by mesotrione, a specific suppressor of KICD.

In conclusion, HMB seems to be an active metabolite of Leu to suppress muscle protein degradation in a starvation model, and the mechanisms may be associated with improved mitochondrial oxidative capacity in muscle cells.

The study entitled "Suppression of protein degradation by leucine requires its conversion to β-hydroxy-β-methyl butyrate in C2C12 myotubes" was published in Aging (Albany NY) (http://dx.doi.org/10.18632/aging.102509).

Contact: Duan Yehui

E-mail: duanyehui@isa.ac.cn

Institute of Subtropical Agriculture, Chinese Academy of Sciences