ß-Hydroxy-ß- methylbutyrate (HM) supplementation stimulates skeletal muscle hypertrophy in rats via the mTOR pathway

Department of Physiology of Nutrition, Federal University of São Paulo (UNIFESP), São Paulo, SP - Brazil. .
Nutrition & Metabolism (Impact Factor: 3.26). 02/2011; 8(1):11. DOI: 10.1186/1743-7075-8-11
Source: PubMed


β-Hydroxy-β-methylbutyrate (HMβ) supplementation is used to treat cancer, sepsis and exercise-induced muscle damage. However, its effects on animal and human health and the consequences of this treatment in other tissues (e.g., fat and liver) have not been examined. The purpose of this study was to evaluate the effects of HMβ supplementation on skeletal muscle hypertrophy and the expression of proteins involved in insulin signalling. Rats were treated with HMβ (320 mg/kg body weight) or saline for one month. The skeletal muscle hypertrophy and insulin signalling were evaluated by western blotting, and hormonal concentrations were evaluated using ELISAs. HMβ supplementation induced muscle hypertrophy in the extensor digitorum longus (EDL) and soleus muscles and increased serum insulin levels, the expression of the mammalian target of rapamycin (mTOR) and phosphorylation of p70S6K in the EDL muscle. Expression of the insulin receptor was increased only in liver. Thus, our results suggest that HMβ supplementation can be used to increase muscle mass without adverse health effects.

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    • "Interestingly, while myotubes treated with MSTN only showed a significant decrease in myotube diameter, this effect was reversed in all three treatment groups (MSTN + Leu, MSTN + HMB, and MSTN + Crea). There is ample evidence to suggest that leucine and HMB are able to increase muscle protein synthesis in vitro and in vivo[26,27,45,46]. Thus, it is difficult to reconcile why MSTN + Leu and MSTN + HMB treatments in the current study did not statistically increase muscle protein synthesis compared to DM/CTL myotubes. "
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    ABSTRACT: The purpose of this study was to examine if L-leucine (Leu), β-hydroxy-β-methylbutyrate (HMB), or creatine monohydrate (Crea) prevented potential atrophic effects of myostatin (MSTN) on differentiated C2C12 myotubes. After four days of differentiation, myotubes were treated with MSTN (10 ng/ml) for two additional days and four treatment groups were studied: 1) 3x per day 10 mM Leu, 2) 3x per day 10 mM HMB, 3) 3x per day 10 mM Crea, 4) DM only. Myotubes treated with DM without MSTN were analyzed as the control condition (DM/CTL). Following treatment, cells were analyzed for total protein, DNA content, RNA content, muscle protein synthesis (MPS, SUnSET method), and fiber diameter. Separate batch treatments were analyzed for mRNA expression patterns of myostatin-related genes (Akirin-1/Mighty, Notch-1, Ski, MyoD) as well as atrogenes (MuRF-1, and MAFbx/Atrogin-1). MSTN decreased fiber diameter approximately 30% compared to DM/CTL myotubes (p < 0.001). Leu, HMB and Crea prevented MSTN-induced atrophy. MSTN did not decrease MPS levels compared to DM/CTL myotubes, but MSTN treatment decreased the mRNA expression of Akirin-1/Mighty by 27% (p < 0.001) and MyoD by 26% (p < 0.01) compared to DM/CTL myotubes. shRNA experiments confirmed that Mighty mRNA knockdown reduced myotube size, linking MSTN treatment to atrophy independent of MPS. Remarkably, MSTN + Leu and MSTN + HMB myotubes had similar Akirin-1/Mighty and MyoD mRNA levels compared to DM/CTL myotubes. Furthermore, MSTN + Crea myotubes exhibited a 36% (p < 0.05) and 86% (p < 0.001) increase in Akirin-1/Mighty mRNA compared to DM/CTL and MSTN-only treated myotubes, respectively. Leu, HMB and Crea may reduce MSTN-induced muscle fiber atrophy by influencing Akirin-1/Mighty mRNA expression patterns. Future studies are needed to examine if Leu, HMB and Crea independently or synergistically affect Akirin-1/Mighty expression, and how Akirin-1/Mighty expression mechanistically relates to skeletal muscle hypertrophy in vivo.
    Journal of the International Society of Sports Nutrition 08/2014; 11(1):38. DOI:10.1186/1550-2783-11-38 · 1.91 Impact Factor
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    • "However, we cannot neglect the significant interaction between DEX and HMB or the exacerbation of blood glucose values late in the experimental period (min 120 from ipGTT) associated with the presence of HMB. In fact, a previous study with rats supplemented with HMB (320 mg·kg BW −1 for 30 days) did not show alteration in the total content of insulinsignaling related proteins, e.g., the serine/threonine kinase (Akt) and the IR, but resulted in the increased mammalian target of rapamycin (mTOR) protein content, as well as phosphorylated serine/threonine kinase of the S6 ribosomal protein (p70S6K) in extensor digitorum longus (EDL) muscles (Pimentel et al. 2011). In agreement with this study, Balage and colleagues (2011) demonstrated that rats supplemented with leucine (4.5% added to the diet for 5 weeks) did not exhibit alteration in insulin-signaling proteins content from skeletal muscle under fasting conditions. "
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    ABSTRACT: Glucocorticoid (GC) excess alters glucose homeostasis and promotes modifications in murinometric and anthropometric parameters in rodents and humans, respectively. β-hydroxy-β-methylbutyrate (HMB), a leucine metabolite, has been proposed as a nutritional strategy for preventing muscle wasting, but few data regarding its effects on glucose homeostasis are available. Here, we analyzed whether the effects of GC excess on glucose homeostasis may be attenuated or exacerbated by the concomitant ingestion of HMB. Adult Wistar rats (90-days-old) were assigned to four groups: (1) vehicle treated (Ctl), (2) dexamethasone (DEX) treated (Dex), (3) HMB treated (Hmb), and (4) DEX plus HMB treated (DexHmb). Dex groups received DEX (1 mg·kg body weight (BW)(-1), intraperitoneal) for 5 consecutive days. HMB groups ingested HMB (320 mg·kg BW(-1), oral gavage) for the same 5 days. HMB ingestion did not attenuate the effects of DEX on food intake and body weight loss, changes in masses of several organs, insulin resistance, and glucose intolerance (p > 0.05). In fact, in DexHmb rats, there was increased fasting glycemia and exacerbated glucose intolerance with the main effect attributed to DEX treatment (p < 0.05). HMB exerted no attenuating effect on plasma triacylglycerol levels from DexHmb rats, but it seems to attenuate the lipolysis induced by β-adrenergic stimulation (20 μmol·L(-1) isoproterenol) in fragments of retroperitoneal adipose tissue from DexHmb rats. Therefore, HMB does not attenuate the diabetogenic characteristics of GC excess. In fact, the data suggest that HMB may exacerbate GC-induced glucose intolerance.
    Applied Physiology Nutrition and Metabolism 11/2013; 38(11):1137-46. DOI:10.1139/apnm-2012-0456 · 2.34 Impact Factor
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    • "Thus, HMB attenuation of muscle and body weight loss in experimental cancer cachexia may rely on HMB-mediated decrease in phosphorylated eIF2a and increase in phosphorylated p70 S6k and phosphorylated mTOR (Aversa et al. 2011). The HMB anabolic properties are consistent with muscle hypertrophy and increase in serum insulin levels, expression of mTOR and phosphorylation of p70 S6k in healthy and sedentary rats (Pimentel et al. 2011). In addition to the anabolic properties above, the increase of muscle glycogen, ATP content and citrate synthase (CS) activity after HMB supplementation to Wistar rats confirm HMB-related changes in oxidative metabolism improving muscle strength generation and performance during intense contractions (Pinheiro et al. 2012). "
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    ABSTRACT: Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. We performed a systematic review of the clinical literature on the effectiveness of HMB supplementation in healthy and pathological conditions (i.e. training programs, aging, acute and chronic diseases, and after bariatric surgery). We reviewed all clinical trials indexed in Medline that tested HMB supplementation as well as all the experimental data regarding HMB intracellular mechanisms of action. Search terms included: randomized controlled trials, controlled clinical trials, single- and double-blind method, HMB, proteolytic pathways, muscle atrophy, cachexia, and training. We found out 13 studies testing HMB in healthy young trained subjects, 11 in healthy young untrained subjects, 9 in patients affected by chronic diseases (i.e. cancer, HIV, chronic obstructive pulmonary disease), and 6 in elderly subjects. The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions.
    Amino Acids 09/2013; 45(6). DOI:10.1007/s00726-013-1592-z · 3.29 Impact Factor
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