Effects of leucine and its metabolite β‐hydroxy‐β‐methylbutyrate on human skeletal muscle protein metabolism

Wilkinson, Daniel J.; Hossain, Tanvir; Hill, Derek Samuel; Phillips, Bethan E.; Crossland, Hannah; Williams, John P.; Loughna, Paul T.; Churchward‐Venne, Tyler A.; Breen, Leigh; Phillips, Stuart M.; Etheridge, Timothy; Rathmacher, John A.; Smith, Kenneth; Szewczyk, Nathaniel J.; Atherton, Philip J.

doi:10.1113/jphysiol.2013.253203

Cited by 415 publications

(449 citation statements)

References 38 publications

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“…This was slightly surprising since mTORC1 activation is associated with inhibition of autophagy (Sandri, 2013), and there is evidence that amino acid ingestion can also prevent elevations in MuRF‐1 ( Trim63 ) and MAFbx ( Fbxo32 ) expression at rest and following exercise (Borgenvik, Apro, & Blomstrand, 2012; Herningtyas et al, 2008). Our in vitro data support in vivo human data reporting no alterations in proteolytic gene expression following ingestion of leucine or its metabolite β‐Hydroxy‐β‐methylbutyrate in healthy young men (Wilkinson et al, 2013), although, since we measured changes in mRNA expression, we cannot discount the possibility that differences may have been observed at an earlier time point.…”

Section: Discussionsupporting

confidence: 82%

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Martin

Turner

Farrington

et al. 2017

Journal Cellular Physiology

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The amino acid leucine is thought to be important for skeletal muscle growth by virtue of its ability to acutely activate mTORC1 and enhance muscle protein synthesis, yet little data exist regarding its impact on skeletal muscle size and its ability to produce force. We utilized a tissue engineering approach in order to test whether supplementing culture medium with leucine could enhance mTORC1 signaling, myotube growth, and muscle function. Phosphorylation of the mTORC1 target proteins 4EBP‐1 and rpS6 and myotube hypertrophy appeared to occur in a dose dependent manner, with 5 and 20 mM of leucine inducing similar effects, which were greater than those seen with 1 mM. Maximal contractile force was also elevated with leucine supplementation; however, although this did not appear to be enhanced with increasing leucine doses, this effect was completely ablated by co‐incubation with the mTOR inhibitor rapamycin, showing that the augmented force production in the presence of leucine was mTOR sensitive. Finally, by using electrical stimulation to induce chronic (24 hr) contraction of engineered skeletal muscle constructs, we were able to show that the effects of leucine and muscle contraction are additive, since the two stimuli had cumulative effects on maximal contractile force production. These results extend our current knowledge of the efficacy of leucine as an anabolic nutritional aid showing for the first time that leucine supplementation may augment skeletal muscle functional capacity, and furthermore validates the use of engineered skeletal muscle for highly‐controlled investigations into nutritional regulation of muscle physiology.

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Section: Discussionsupporting

confidence: 82%

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Martin

Turner

Farrington

et al. 2017

Journal Cellular Physiology

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“…Leucine concentrations in blood plasma and muscles were not altered after oral HMB consumption in humans 12. We suppose that the difference between the results of animal and human studies is due to the dose, duration, and route of HMB administration.…”

Section: Effects Of Hmbmentioning

confidence: 73%

“…The HMB stimulates protein synthesis via mTOR, a protein kinase that has a central role in controlling mRNA translation efficiency 12. Recently, Girón et al .…”

Section: Effects Of Hmbmentioning

confidence: 99%

Beta‐hydroxy‐beta‐methylbutyrate supplementation and skeletal muscle in healthy and muscle‐wasting conditions

Holeček

2017

J cachexia sarcopenia muscle

200

154

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Beta‐hydroxy‐beta‐methylbutyrate (HMB) is a metabolite of the essential amino acid leucine that has been reported to have anabolic effects on protein metabolism. The aims of this article were to summarize the results of studies of the effects of HMB on skeletal muscle and to examine the evidence for the rationale to use HMB as a nutritional supplement to exert beneficial effects on muscle mass and function in various conditions of health and disease.The data presented here indicate that the beneficial effects of HMB have been well characterized in strength‐power and endurance exercise. HMB attenuates exercise‐induced muscle damage and enhances muscle hypertrophy and strength, aerobic performance, resistance to fatigue, and regenerative capacity. HMB is particularly effective in untrained individuals who are exposed to strenuous exercise and in trained individuals who are exposed to periods of high physical stress. The low effectiveness of HMB in strength‐trained athletes could be due to the suppression of the proteolysis that is induced by the adaptation to training, which may blunt the effects of HMB. Studies performed with older people have demonstrated that HMB can attenuate the development of sarcopenia in elderly subjects and that the optimal effects of HMB on muscle growth and strength occur when it is combined with exercise. Studies performed under in vitro conditions and in various animal models suggest that HMB may be effective in treatment of muscle wasting in various forms of cachexia. However, there are few clinical reports of the effects of HMB on muscle wasting in cachexia; in addition, most of these studies evaluated the therapeutic potential of combinations of various agents. Therefore, it has not been possible to determine whether HMB was effective or if there was a synergistic effect. Although most of the endogenous HMB is produced in the liver, there are no reports regarding the levels and the effects of HMB supplementation in subjects with liver disease. Several studies have suggested that anabolic effects of HMB supplementation on skeletal muscle do not occur in healthy, non‐exercising subjects.It is concluded that (i) HMB may be applied to enhance increases in the mass and strength of skeletal muscles in subjects who exercise and in the elderly and (ii) studies examining the effects of HMB administered alone are needed to obtain conclusions regarding the specific effectiveness in attenuating muscle wasting in various muscle‐wasting disorders.

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“…The cytosolic enzyme α‐ketoisocaproate dioxygenase (or 4‐hydroxyphenylpyruvate dioxygenase)48 produces HMB from L‐Leu. KICD is mainly expressed in the liver, kidney, and neurons, but it is absent in muscle tissues,49 although in a recent study,41 this enzyme has been shown to be expressed in skeletal muscle at low levels. This enzyme provides a direct pathway for the synthesis of HMB, and this pathway accounts for up to 5% of the L‐Leu catabolism in humans 23…”

Section: Discussionmentioning

confidence: 96%

“…HMB has positive effects promoting strength and lean body mass in sport performance 40. Also, as a therapeutic supplement (especially in atrophic conditions), HMB stimulates muscle protein synthesis and reduces protein degradation 9, 17, 18, 21, 41. The increase in protein synthesis by HMB has been correlated with the activation of mTOR and two of its substrates 4E‐BP1 and S6K1, proteins involved in the translation of mRNA and protein synthesis 14, 40…”

Section: Discussionmentioning

confidence: 99%

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundL‐Leu and its metabolite β‐hydroxy‐β‐methylbutyrate (HMB) stimulate muscle protein synthesis enhancing the phosphorylation of proteins that regulate anabolic signalling pathways. Alterations in these pathways are observed in many catabolic diseases, and HMB and L‐Leu have proven their anabolic effects in in vivo and in vitro models. The aim of this study was to compare the anabolic effects of L‐Leu and HMB in myotubes grown in the absence of any catabolic stimuli.MethodsStudies were conducted in vitro using rat L6 myotubes under normal growth conditions (non‐involving L‐Leu‐deprived conditions). Protein synthesis and mechanistic target of rapamycin signalling pathway were determined.ResultsOnly HMB was able to increase protein synthesis through a mechanism that involves the phosphorylation of the mechanistic target of rapamycin as well as its downstream elements, pS6 kinase, 4E binding protein‐1, and eIF4E. HMB was significantly more effective than L‐Leu in promoting these effects through an activation of protein kinase B/Akt. Because the conversion of L‐Leu to HMB is limited in muscle, L6 cells were transfected with a plasmid that codes for α‐keto isocaproate dioxygenase, the key enzyme involved in the catabolic conversion of α‐keto isocaproate into HMB. In these transfected cells, L‐Leu was able to promote protein synthesis and mechanistic target of rapamycin regulated pathway activation equally to HMB. Additionally, these effects of leucine were reverted to a normal state by mesotrione, a specific inhibitor of α‐keto isocaproate dioxygenase.ConclusionOur results suggest that HMB is an active L‐Leu metabolite able to maximize protein synthesis in skeletal muscle under conditions, in which no amino acid deprivation occurred. It may be proposed that supplementation with HMB may be very useful to stimulate protein synthesis in wasting conditions associated with chronic diseases, such as cancer or chronic heart failure.

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Effects of leucine and its metabolite β‐hydroxy‐β‐methylbutyrate on human skeletal muscle protein metabolism

Cited by 415 publications

References 38 publications

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Beta‐hydroxy‐beta‐methylbutyrate supplementation and skeletal muscle in healthy and muscle‐wasting conditions

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

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