Effect of endurance training and branched-chain amino acids on the signaling for muscle protein synthesis in CKD model rats fed a low-protein diet

Abstract

A low-protein diet (LPD) protects against the progression of renal injury in patients with chronic kidney disease (CKD). However, LPD may accelerate muscle wasting in these patients. Both exercise and branched-chain amino acids (BCAA) are known to increase muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) pathway. The aim of this study was to investigate whether endurance exercise and BCAA play a role for increasing muscle protein synthesis in LPD-fed CKD (5/6 nephrectomized) rats. Both CKD and sham rats were pair-fed on LPD or LPD fortified with a BCAA diet (BD), and approximately one-half of the animals in each group was subjected to treadmill exercise (15 m/min, 1 h/day, 5 days/wk). After 7 wk, renal function was measured, and soleus muscles were collected to evaluate muscle protein synthesis. Renal function did not differ between LPD- and BD-fed CKD rats, and the treadmill exercise did not accelerate renal damage in either group. The treadmill exercise slightly increased the phosphorylation of p70s6 kinase, a marker of mTOR activity, in the soleus muscle of LPD-fed CKD rats compared with the sham group. Furthermore, BCAA supplementation of the LPD-fed, exercise-trained CKD rats restored the phosphorylation of p70s6 kinase to the same level observed in the sham group; however, the corresponding induced increase in muscle protein synthesis and muscle mass was marginal. These results indicate that the combination of treadmill exercise and BCAA stimulates cell signaling to promote muscle protein synthesis; however, the implications of this effect for muscle growth remain to be clarified.

Regular exercise and branched‐chain amino acids prevent ischemic acute kidney injury‐related muscle wasting in mice

“…Regular exercise exerts a positive effect on muscle mass in CKD by enhancing protein synthesis and suppressing proteolysis via UPS activation (Bacurau et al., 2016; De Moraes et al., 2018; Sakai et al., 2017; Yoshida et al., 2017). For instance, exercise has been found to increase PGC‐1α mRNA expression, a master regulator of mitochondrial biosynthesis and energy metabolism (Cantó & Auwerx, 2009; Wu et al., 1999).…”

“…Since BCAA may cause glomerular hyperfiltration and aggravate renal prognosis (Pillai et al., 2019), few studies have examined the effect of BCAA alone on muscle in renal injury models. Yoshida et al reported (Yoshida et al., 2017) that BCAA administration alone was ineffective against CKD‐induced muscle wasting in 5/6 nephrectomized rats, but had a synergistic effect with exercise without the progression in CKD. Similarly, in a human study, BCAA, when used in combination with exercise, enhanced phosphorylation of mammalian target of rapamycin (mTOR) complex 1 and ribosomal protein S6 kinase (S6K) beta‐1, and decreased atrogin‐1 and MuRF‐1 mRNA levels, in vastus lateralis muscle (Borgenvik, Apró, & Blomstrand, 2012).…”

“…In preliminary study, this was the maximum load, which the mice with AKI could run. Drinking water for each cage was prepared with 1.0% BCAA (leucine:isoleucine:valine, 3:1:1) on day 1 and 0.6% BCAA thereafter, as described previously (Baptista et al., 2013; Yoshida et al., 2017).…”

“…The samples were then cut into 10 μm thick sections, stained with hematoxylin and eosin. The CSA of 200 myofibers per sample was measured using ImageJ software (National Institutes of Health) and reported as the mean (Yoshida et al., 2017).…”

“…In addition, early rehabilitation twice per day for 30 min during the first week of septic shock has been shown to prevent declining myofiber cross‐sectional area (CSA) (Hickmann et al., 2018). Although oral BCAA supplementation alone was unable to ameliorate muscle wasting in CKD rats with 5/6 nephrectomy (Yoshida et al., 2017), no studies have yet examined whether early intervention with combined exercise and BCAA supplementation could prevent AKI‐related muscle wasting, or have elucidated the associated mechanisms.…”