Dexamethasone and BCAA Failed to Modulate Muscle Mass and mTOR Signaling in GH-Deficient Rats

Abstract

Branched-chain amino acids (BCAAs) and IGF-I, the secretion of which is stimulated by growth hormone (GH), prevent muscle atrophy. mTOR plays a pivotal role in the protective actions of BCAA and IGF-1. The pathway by which BCAA activates mTOR is different from that of IGF-1, which suggests that BCAA and GH work independently. We tried to examine whether BCAA exerts a protective effect against dexamethasone (Dex)-induced muscle atrophy independently of GH using GH-deficient spontaneous dwarf rats (SDRs). Unexpectedly, Dex did not induce muscle atrophy assessed by the measurement of cross-sectional area (CSA) of the muscle fibers and did not increase atrogin-1, MuRF1 and REDD1 expressions, which are activated during protein degradation. Glucocorticoid (GR) mRNA levels were higher in SDRs compared to GH-treated SDRs, indicating that the low expression of GR is not the reason of the defect of Dex’s action in SDRs. BCAA did not stimulate the phosphorylation of p70S6K or 4E-BP1, which stimulate protein synthesis. BCAA did not decrease the mRNA level of atrogin-1 or MuRF1. These findings suggested that Dex failed to modulate muscle mass and that BCAA was unable to activate mTOR in SDRs because these phosphorylations of p70S6K and 4E-BP1 and the reductions of these mRNAs are regulated by mTOR. In contrast, after GH supplementation, these responses to Dex were normalized and muscle fiber CSA was decreased by Dex. BCAA prevented the Dex-induced decrease in CSA. BCAA increased the phosphorylation of p70S6K and decreased the Dex-induced elevations of atrogin-1 and Bnip3 mRNAs. However, the amount of mTORC1 components including mTOR was not decreased in the SDRs compared to the normal rats. These findings suggest that GH increases mTORC1 activity but not its content to recover the action of BCAA in SDRs and that GH is required for actions of Dex and BCAA in muscles.

Omega-3 multiple effects increasing glucocorticoid-induced muscle atrophy: autophagic, AMPK and UPS mechanisms

“…However, after 5 days, REDD‐2 expression was elevated in rats treated with DEXA without changes in REDD‐1 (Nishida et al. ). These results corroborate our results on REDD1/2 expression regarding DEXA administration (without N‐3 supplemented), which showed a REDD1/2 time‐dependent action on glucocorticoid‐induced muscle atrophy.…”

Succinate promotes skeletal muscle protein synthesis via Erk1/2 signaling pathway

“…Classically, hormones and nutrients, for example insulin-like growth factors-1 (IGF-1) and amino acids, are crucial regulator for skeletal muscle protein synthesis ( 21 ). It should be emphasized that several metabolites of animo acids and TCA cycle, such as α-ketoisocaproate, β-hydroxy-β-methylbutyrate and α-ketoglutarate, have also been identified to enhance skeletal muscle growth by increasing protein synthesis and inhibiting protein degradation ( 3 , 22 , 23 ).…”

Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

“…Lack of GH in GH-deficient spontaneous dwarf rats (abnormally spliced GH gene) attenuated the dexamethasone-induced increase in REDD1 mRNA in the extensor digitorum longus (EDL) muscle (90). Replacement of GH for 14 days using implanted osmotic minipumps restored the ability of dexamethasone to increase REDD1 expression (90).…”

“…Lack of GH in GH-deficient spontaneous dwarf rats (abnormally spliced GH gene) attenuated the dexamethasone-induced increase in REDD1 mRNA in the extensor digitorum longus (EDL) muscle (90). Replacement of GH for 14 days using implanted osmotic minipumps restored the ability of dexamethasone to increase REDD1 expression (90). Future work is needed to determine whether REDD1 is a viable target for attenuating the negative impact of glucocorticoids on skeletal muscle health in humans and whether anabolic hormones are a potential countertherapy.…”