Effects of creatine supplementation on muscle wasting and glucose homeostasis in rats treated with dexamethasone

We aimed to investigate the possible role of creatine (CR) supplementation in counteracting dexamethasone-induced muscle wasting and insulin resistance in rats. Also, we examined whether CR intake would modulate molecular pathways involved in muscle remodeling and insulin signaling. Animals were randomly divided into four groups: (1) dexamethasone (DEX); (2) control pair-fed (CON-PF); (3) dexamethasone plus CR (DEX-CR); and (4) CR pair-fed (CR-PF). Dexamethasone (5 mg/kg/day) and CR (5 g/kg/day) were given via drinking water for 7 days. Plantaris and extensor digitorum longus (EDL) muscles were removed for analysis. Plantaris and EDL muscle mass were significantly reduced in the DEX-CR and DEX groups when compared with the CON-PF and CR-PF groups (P < 0.05). Dexamethasone significantly decreased phospho-Ser(473)-Akt protein levels compared to the CON-PF group (P < 0.05) and CR supplementation aggravated this response (P < 0.001). Serum glucose was significantly increased in the DEX group when compared with the CON-PF group (DEX 7.8 +/- A 0.6 vs. CON-PF 5.2 +/- A 0.5 mmol/l; P < 0.05). CR supplementation significantly exacerbated hyperglycemia in the dexamethasone-treated animals (DEX-CR 15.1 +/- A 2.4 mmol/l; P < 0.05 vs. others). Dexamethasone reduced GLUT-4 translocation when compared with the CON-PF and CR-PF (P < 0.05) groups and this response was aggravated by CR supplementation (P < 0.05 vs. others). In conclusion, supplementation with CR resulted in increased insulin resistance and did not attenuate muscle wasting in rats treated with dexamethasone. Given the contrast with the results of human studies that have shown benefits of CR supplementation on muscle atrophy and insulin sensitivity, we suggest caution when extrapolating this animal data to human subjects.

Mechanotransduction pathways in skeletal muscle hypertrophy

In the last decade, molecular biology has contributed to define some of the cellular events that trigger skeletal muscle hypertrophy. Recent evidence shows that insulin like growth factor 1/phosphatidyl inositol 3-kinase/protein kinase B (IGF-1/PI3K/Akt) signaling is not the main pathway towards load-induced skeletal muscle hypertrophy. During load-induced skeletal muscle hypertrophy process, activation of mTORC1 does not require classical growth factor signaling. One potential mechanism that would activate mTORC1 is increased synthesis of phosphatidic acid (PA). Despite the huge progress in this field, it is still early to affirm which molecular event induces hypertrophy in response to mechanical overload. Until now, it seems that mTORC1 is the key regulator of load-induced skeletal muscle hypertrophy. On the other hand, how mTORC1 is activated by PA is unclear, and therefore these mechanisms have to be determined in the following years. The understanding of these molecular events may result in promising therapies for the treatment of muscle-wasting diseases. For now, the best approach is a good regime of resistance exercise training. The objective of this point-of-view paper is to highlight mechanotransduction events, with focus on the mechanisms of mTORC1 and PA activation, and the role of IGF-1 on hypertrophy process.

Effects of leucine supplementation and resistance exercise on dexamethasone-induced muscle atrophy and insulin resistance in rats

Objective: We aimed to evaluate the effects of resistance exercise (RE) and leucine (LEU) supplementation on dexamethasone (DEXA)-induced muscle atrophy and insulin resistance. Methods: Male Wistar rats were randomly divided into DEXA(DEX), DEXA + RE (DEX-RE), DEXA + LEU (DEX-LEU), and DEXA + RE + LEU (DEX-RE-LEU) groups. Each group received DEXA 5 mg . kg(-1) . d(-1) for 7 d from drinking water and were pair-fed to the DEX group; LEU-supplemented groups received 0.135 g . kg(-1) . d(-1) through gavage for 7 d; the RE protocol was based on three sessions of squat-type exercise composed by three sets of 10 repetitions at 70% of maximal voluntary strength capacity. Results: The plantaris mass was significantly greater in both trained groups compared with the non-trained groups. Muscle cross-sectional area and fiber areas did not differ between groups. Both trained groups displayed significant increases in the number of intermediated fibers (IIa/IIx), a decreased number of fast-twitch fibers (IIb), an increased ratio of the proteins phospho(Ser2448)/ total mammalian target of rapamycin and phospho(Thr389)/total 70-kDa ribosomal protein S6 kinase. and a decreased ratio of phospho(Ser253)/total Forkhead box protein-3a. Plasma glucose was significantly increased in the DEX-LEU group compared with the DEX group and RE significantly decreased hyperglycemia. The DEX-LEU group displayed decreased glucose transporter-4 translocation compared with the DEX group and RE restored this response. LEU supplementation worsened insulin sensitivity and did not attenuate muscle wasting in rats treated with DEXA. Conversely, RE modulated glucose homeostasis and fiber type transition in the plantaris muscle. Conclusion: Resistance exercise but not LEU supplementation promoted fiber type transition and improved glucose homeostasis in DEXA-treated rats. (C) 2012 Elsevier Inc. All rights reserved.

Ursolic acid directly promotes protein accretion in myotubes but does not affect myoblast proliferation

Ursolic acid (UA) has been recently proposed as a potential candidate for the treatment of muscle wasting conditions because of its protein sparring/anabolic effects. Despite this finding, it is unknown whether this response is the consequence of a direct effect on the muscle fibre or if it is mediated by neural or other systemic factors. In the present study, we sought to determine if UA has direct effects in skeletal muscle cells, whether it can increase myoblast proliferation and whether UA can become myotoxic at higher doses. Our results demonstrate that UA directly promoted protein accretion in cultured myotubes but did not modulate myoblast proliferation. At higher doses, UA compromised cell viability in both myoblasts and myotubes. We conclude that the anabolic properties of UA seen in vivo and in vitro are likely a direct effect on the muscle cell, but at higher doses, the benefits decline in favour of a myotoxic outcome. Copyright (C) 2012 John Wiley & Sons, Ltd.

Myostatin: genetic variants, therapy and gene doping

Since its discovery, myostatin (MSTN) has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.