Leucine minimizes denervation-induced skeletal muscle atrophy of rats through akt/mtor signaling pathways

Abstract

The aim of the present study was to evaluate the effect of leucine treatment (0.30 mM) on muscle weight and signaling of myoproteins related to synthesis and degradation pathways of soleus muscle following seven days of complete sciatic nerve lesion. Wistar rats (n = 24) of 3–4 months of age (192 ± 23 g) were used. The animals were randomly distributed into four experimental groups (n = 6/group): control, treated with leucine (L), denervated (D) and denervated treated with leucine (DL). Dependent measures were proteins levels of AKT, AMPK, mTOR, and ACC performed by Western blot. Leucine induced a reduction in the phosphorylation of AMPK (p < 0.05) by 16% in the L and by 68% in the DL groups as compared with control group. Denervation increased AMPK by 24% in the D group as compared with the control group (p < 0.05). AKT was also modulated by denervation and leucine treatment, highlighted by the elevation of AKT phosphorylation in the D (65%), L (98%) and DL (146%) groups as compared with the control group (p < 0.05). AKT phosphorylation was 49% higher in the D group as compared with the DL group. Furthermore, denervation decreased mTOR phosphorylation by 29% in the D group as compared with the control group. However, leucine treatment induced an increase of 49% in the phosphorylation of mTOR in the L group as compared with the control group, and an increase of 154% in the DL as compared with the D group (p < 0.05). ACC phosphorylation was 20% greater in the D group than the control group. Furthermore, ACC in the soleus was 22% lower in the in the L group and 50% lower in the DL group than the respective control group (p < 0.05). In conclusion, leucine treatment minimized the deleterious effects of denervation on rat soleus muscle by increasing anabolic (AKT and mTOR) and decreasing catabolic (AMPK) pathways. These results may be interesting for muscle recovery following acute denervation, which may contribute to musculoskeletal rehabilitation after denervation.

Protective effect of branched chain amino acids on hindlimb suspension-induced muscle atrophy in growing rats

“…This result agrees with some human studies showing that infusion of BCAA suppressed muscle protein breakdown without increasing protein synthesis, although species differences may be present [ 39 – 40 ]. In contrast with our results, leucine increased the phosphorylation of Akt and mTOR against denervation induced muscle atrophy in middle aged rats [ 29 ]. These results suggest that although BCAA administration did not increase the levels of Akt1 and mTOR mRNA, it has the potential to affect the activation of Akt1 and mTOR at the protein level.…”

“…Furthermore, it is well known that BCAA plays a pivotal role in protein synthesis through the direct activation of mTOR without the activation of upstream signaling molecules like IGF-1 and Akt1 [ 28 ]. However, recent study shows that leucine activates Akt as well as mTOR [ 29 ]. Akt, also known as protein kinase B (PKB), has emerged as a critical mediator of mTOR activity.…”

Leucine stimulates PPARβ/δ-dependent mitochondrial biogenesis and oxidative metabolism with enhanced GLUT4 content and glucose uptake in myotubes

“…While p-Akt content was elevated, the difference between treatments was not significant. Despite this observation, leucine has previously been repeatedly shown to enhance insulin signaling through increased Akt activity [24][25][26][27][28][29][30]. This is of profound significance, as GLUT4 membrane content is tightly regulated by insulin signaling following carbohydrate-rich meals.…”

GCN2 deficiency protects mice from denervation-induced skeletal muscle atrophy via inhibiting FoxO3a nuclear translocation

“…Several recent clinical studies have indicated that dietary supplementation with branched-chain amino acids (BCAA), particularly with leucine, is an effective anti-atrophic therapy (Bauer et al, 2015 ; Tsien et al, 2015 ; English et al, 2016 ). In animal models, BCAA can prevent denervation (Ribeiro et al, 2015 ), hindlimb suspension (Maki et al, 2012 ; Jang et al, 2015 ) or dexamethasone-induced (Yamamoto et al, 2010 ) muscle atrophy. General control nonderepressible 2 kinase (GCN2) is a well-known amino-acid sensor.…”