beta-Hydroxy beta-methylbutyric acid

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β-Hydroxy β-methylbutyric acid
Structure diagram, conjugate acid
Structure diagram, conjugate base
Top: β-Hydroxy β-methylbutyric acid
Bottom: Calcium hydroxymethylbutyrate
Systematic (IUPAC) name
3-hydroxy-3-methylbutanoic acid
Clinical data
Routes of
administration
Oral (by mouth)
Legal status
Legal status
  • US: OTC
  • UN: Unscheduled
Pharmacokinetic data
Metabolites HMB-CoA, HMG-CoA, mevalonate, cholesterol, acetoacetyl-CoA, acetyl-CoA
Onset of action HMB-FA: 30–60 minutes[1]
HMB-Ca: 1–2 hours[1]
Biological half-life HMB-FA: 3 hours[1]
HMB-Ca: 2.5 hours[1]
Excretion Renal (10–40% excreted)[1][2]
Identifiers
CAS Number 625-08-1 YesY
ATC code none
PubChem CID 69362
ChemSpider 62571 YesY
UNII 3F752311CD YesY
ChEBI CHEBI:37084 YesY
Synonyms Conjugate acid form:
β-Hydroxyisovaleric acid
3-Hydroxyisovaleric acid
Conjugate base form:
Hydroxymethylbutyrate
Chemical data
Formula C5H10O3
Molar mass 118.131 g/mol

β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base β-hydroxy β-methylbutyrate (hydroxymethylbutyrate, HMB), is a dietary supplement and naturally occurring metabolite in humans that is used in medicine as a treatment for muscle wasting conditions and by athletes as a performance-enhancing substance.[3][4][5] HMB is used in medicine as an adjunct therapy in conjunction with physical exercise to inhibit muscle wasting.[3][5] It is also used by athletes to augment exercise-induced gains in muscle hypertrophy, muscle strength, and lean body mass, reduce exercise-induced skeletal muscle damage, and expedite recovery from high-intensity exercise.[1][3][4][6]

There appear to be no issues with safety (i.e., no adverse effects) from long-term use as a nutritional supplement in young or old individuals.[1][4][7]

HMB is a metabolite of L-leucine that is produced in the body through oxidation of the ketoacid of L-leucine (α-ketoisocaproic acid).[1][8] It is present in insignificant quantities in various foods, such as citrus fruits (e.g., grapefruit), catfish, and milk.[3][9][10] HMB is also sold as a dietary supplement in the free acid form and as a monohydrated calcium salt of the conjugate base.[1][11]

As of 2015, HMB was not tested for or banned by any sporting organization in the United States or internationally.[4] A NCAA study from 2006 found that 1.9% of college student athletes used HMB as a dietary supplement and the use of HMB among these athletes appears to be increasing.[4][12]

Available forms[edit]

HMB is available as an over-the-counter dietary supplement in the free acid form, β-hydroxy β-methylbutyric acid (HMB-FA), and as a monohydrated calcium salt of the conjugate base, calcium β-hydroxy β-methylbutyrate monohydrate (HMB-Ca).[11] After ingestion, HMB-Ca is converted to β-hydroxy β-methylbutyrate following dissociation of the calcium moiety in the gut.[1]

Uses[edit]

Medical[edit]

HMB is used as a treatment for preserving lean body mass in muscle wasting conditions, particularly sarcopenia, and is often employed as an adjunct therapy in conjunction with physical exercise.[3][5] Based upon a meta-analysis of seven randomized controlled trials, HMB supplementation has efficacy as a treatment for preserving lean muscle mass in older adults.[5] It also appears to be an effective treatment for reducing muscle atrophy from bed rest.[3][5][13] It does not appear to significantly affect fat mass in older adults.[5] More research is needed to determine the precise effects on muscle strength and function in this age group.[5] HMB has also shown promise as a treatment for cancer cachexia, but further research is required to establish efficacy.[3][14][15]

As a treatment for muscle wasting, it is usually taken as a single 3 gram dose, once per day;[3] however, the optimal dosing regimen is one 1 gram dose, three times a day, since this ensures elevated plasma concentrations of HMB throughout the day.[3]

Enhancing performance[edit]

When combined with an appropriate exercise program, dietary supplementation with HMB dose-dependently augments gains in muscle hypertrophy (i.e., the size of a muscle),[4][5] muscle strength,[3][4][16] and lean body mass,[3][4][16] reduces exercise-induced skeletal muscle damage,[note 1][4][5][16] and may expedite recovery from high-intensity exercise.[1][4] HMB produces these effects by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of the proteasome in skeletal muscles.[3][13]

The inhibition of exercise-induced skeletal muscle damage by HMB is affected by the time that it is used relative to exercise.[1][4] The greatest reduction in skeletal muscle damage from a single bout of exercise has been shown to occur when HMB-Ca is ingested 1–2 hours prior to exercise or HMB-FA is ingested 30–60 minutes prior to exercise.[1]

Side effects[edit]

The safety profile of HMB in humans and animals has been well-established in medical reviews.[3][4][7] No adverse effects in humans have been reported when it is taken in doses of 3 grams/day for up to a year.[3][4][7]

Pharmacology[edit]

Pharmacodynamics[edit]

As of May 2016, components of the signaling cascade that mediates the HMB-induced increase in human skeletal muscle protein synthesis have been identified in vivo.[5][17] Similar to L-leucine,[note 2] HMB has been shown to increase protein synthesis in human skeletal muscle via the phosphorylation of mTOR and subsequent activation of mTORC1, which leads to protein biosynthesis in the ribosome via phosphorylation of mTORC1's immediate targets (the p70S6 kinase and the translation initiation factor 4EBP1).[13][17][19] Chronic supplementation with HMB for one month in rats has also been shown to increase growth hormone and IGF-1 signaling through their associated receptors in certain non-muscle tissues via an unknown mechanism, in turn promoting protein synthesis through increased mTOR phosphorylation.[1][3][20] As of April 2016, it is not clear if long-term supplementation with HMB in humans produces a similar increase in growth hormone and IGF-1 signaling in skeletal muscle or any other tissues.[1][3]

As of May 2016, the signaling cascade that mediates the HMB-induced reduction in muscle protein breakdown has not been identified in living humans, although it is well-established that it attenuates proteolysis in vivo.[5][17] Unlike L-leucine,[note 3] HMB attenuates muscle protein breakdown in an insulin-independent manner in humans.[17] HMB is believed to reduce muscle protein breakdown in humans by inhibiting the 19S and 20S subunits of the ubiquitin–proteasome system in skeletal muscle and by inhibiting apoptosis of myonuclei in muscle cells via unidentified mechanisms.[3][17][19]

HMB has been shown to stimulate the proliferation, differentiation, and fusion of human myosatellite cells in vitro, which potentially increases the regenerative capacity of skeletal muscle, by increasing the protein expression of certain myogenic regulatory factors (e.g., myoD and myogenin) and gene transcription factors (i.e., MEF2).[1][7][21] HMB-induced human myosatellite cell proliferation in vitro is mediated through phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2.[7][20][21] HMB-induced human myosatellite differentiation and accelerated fusion of myosatellite cells into muscle tissue in vitro is mediated through phosphorylation of the protein kinase Akt.[7][20][21] HMB has also been shown to induce phosphorylation of ERK1, ERK2, and Akt, up-regulate MEF2 expression, and activate mechanistic target of rapamycin complex 2 (mTORC2) in mouse neuro2a cells in vitro.[22]

Signaling cascade diagram
Diagram of the molecular signaling cascades that are involved in myofibrillar muscle protein synthesis and mitochondrial biogenesis in response to physical exercise and specific amino acids or their derivatives (primarily L-leucine and HMB).[13]
Graph of muscle protein synthesis vs time
Resistance training stimulates myofibrillar muscle protein synthesis for a period of up to 48 hours following exercise (shown by dotted line).[23] Ingestion of a protein-rich meal at any point during this period will augment the exercise-induced increase in muscle protein synthesis (shown by solid lines).[23]

Pharmacokinetics[edit]

Absorption kinetics from ingesting 1 gram of calcium vs free acid forms of HMB.[1]
This graph shows the number of micromoles of HMB in a liter of blood plasma over time.

The free acid (HMB-FA) and monohydrated calcium salt (HMB-Ca) forms of HMB have different pharmacokinetics.[1][11] HMB-FA is more readily absorbed into the bloodstream and has a longer elimination half-life (3 hours) relative to HMB-Ca (2.5 hours).[1][11] The plasma clearance of HMB-FA, which reflects tissue uptake and utilization, is roughly 25–40% higher than the clearance of HMB-Ca as well.[1][11] The fraction of an ingested dose that is excreted in urine does not differ between the two forms.[1]

The magnitude and time at which the peak plasma concentration of HMB occurs depends on the dose and concurrent food intake when the HMB-Ca dosage form is consumed.[1] Higher HMB-Ca doses increase the rate of absorption, resulting in a peak plasma HMB level (Cmax) that is disproportionately greater than expected of a linear dose-response relationship and which occurs sooner relative to lower doses.[note 4][1] Consumption of HMB-Ca with sugary substances slows the rate of HMB absorption, resulting in a lower peak plasma HMB level that occurs later.[note 5][1]

HMB is eliminated via the kidneys, with roughly 10–40% of an ingested dose being excreted unchanged in urine.[1][2] The remaining 60–90% of the dose is retained in tissues or excreted as HMB metabolites.[1][2] The fraction of a given dose of HMB that is excreted unchanged in urine increases with the dose.[note 6][1]

Biosynthesis[edit]

Human metabolic pathway for HMB and isovaleryl-CoA, relative to L-leucine.[1][2][24] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[1][2][24]

HMB is synthesized in the human body through the metabolism of L-leucine, a branched-chain amino acid.[24] In healthy individuals, approximately 60% of dietary L-leucine is metabolized after several hours, with roughly 5% (2–10% range) of dietary L-leucine being converted to HMB.[2][3][24] Around 40% of dietary L-leucine is converted to acetyl-CoA, which is subsequently used in the synthesis of other compounds.[24]

The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate (α-KIC).[2][24] α-KIC is mostly metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA.[2][24] Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to β-methylcrotonoyl-CoA (MC-CoA), which is used in the synthesis of acetyl-CoA and other compounds.[24] During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme,[25][26][27] which convert MC-CoA into HMB-CoA and HMB-CoA into HMB respectively.[27] A relatively small amount of α-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (KIC dioxygenase), which converts α-KIC to HMB.[2][24][28] In healthy individuals, this minor pathway – which involves the conversion of L-leucine to α-KIC and then HMB – is the predominant route of HMB synthesis.[2][24]

A small fraction of L-leucine metabolism – less than 5% in all tissues except the testes where it accounts for about 33% – is initially catalyzed by leucine aminomutase, producing β-leucine, which is subsequently metabolized into β-ketoisocaproate (β-KIC), β-ketoisocaproyl-CoA, and then acetyl-CoA by a series of uncharacterized enzymes.[24][29] HMB could be produced via certain metabolites that are generated along this pathway, but as of 2015 the associated enzymes and reactions involved are not known.[24]

Metabolism[edit]

The metabolism of HMB is initially catalyzed by an uncharacterized enzyme which converts it to HMB-CoA.[24][26] HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing MC-CoA or hydroxymethylglutaryl-CoA (HMG-CoA) respectively.[2][24] MC-CoA is then converted by the enzyme methylcrotonyl-CoA carboxylase to methylglutaconyl-CoA (MG-CoA), which is subsequently converted to HMG-CoA by methylglutaconyl-CoA hydratase.[2][24][29] HMG-CoA is then cleaved into to acetyl-CoA and acetoacetate by HMG-CoA lyase or used in the production of cholesterol via the mevalonate pathway.[2][24]

Physical and chemical properties[edit]

Synthesis[edit]

β-Hydroxy-β-methylbutyric acid is can be prepared by the oxidation of diacetone alcohol with sodium hypochlorite (NaOCl), more commonly known as bleach.[30][31] Diacetone alcohol in turn may be prepared through the aldol condensation of acetone. Alternatively HMB can be prepared through microbial oxidation of β-methylbutyric acid by the fungus Galactomyces reessii.[32]

HMB synthesis diagram
β-hydroxy β-methylbutyric acid
Synthesis of β-hydroxy β-methylbutyric acid

Detection in body fluids[edit]

HMB concentrations measured in healthy individuals
Biofluid Age group Concentration Sources
Mean Range Units
Blood Adults (18+) 4.0 0–10.0 μM [33]
CSF Adults (18+) 4.0 2.0–6.0 μM [33]
Breast milk Adults (18+) 42–164 μg/L [8]
Urine Adults (18+) 3.2–25.0 μmol/mmol creatinine [33]
Urine Children (1–13) 0–64.4 μmol/mmol creatinine [33]

Endogenously synthesized HMB has been detected and quantified in several human biofluids using nuclear magnetic resonance spectroscopy (NMR), liquid chromatography–mass spectrometry (LC–MS), and gas chromatography–mass spectrometry (GC–MS) methods.[8][33] In the blood plasma and cerebrospinal fluid (CSF) of healthy adults, the average molar concentration of HMB has been quantified at 4.0 μM.[33] In the urine of healthy individuals of any age, the excreted urinary concentration of HMB has been quantified in a range of 0–68 μmol/mmol creatinine.[33] In the breast milk of healthy lactating women, HMB and L-leucine have been quantified in ranges of 42–164 μg/L and 2.1–88.5 mg/L.[8] In comparison, HMB has been detected and quantified in the milk of healthy cows at a concentration of <20–29 μg/L.[10] This concentration is far too low to be an adequate dietary source of HMB, but milk products could be fortified with HMB to confer benefits to skeletal muscle.[10]

In a study where participants consumed 2.42 grams of HMB-FA while fasting, the average plasma HMB concentration increased from a basal level of 5.1 μM to 408 μM after 30 minutes.[17] At 150 minutes post-ingestion, the average plasma HMB concentration among participants was quantified at 275 μM.[17]

Abnormal HMB concentrations in urine and blood plasma have been noted in several disease states where it may serve as a diagnostic biomarker, particularly in the case of metabolic disorders.[33] The following table lists some of these disorders along with the associated HMB concentrations detected in urine or blood plasma.[33]

Abnormal HMB concentrations measured in disease states
Medical condition[note 7] Biofluid Age group Concentration Sources
Mean Range Units
Biotinidase deficiency Blood Adults (18+) 9.5 0–19.0 μM [33]
Biotinidase deficiency Blood Children (1–13) 88.0 10.0–166.0 μM [33]
Biotinidase deficiency Urine Children (1–13) 275.0 50.0–500.0 μmol/mmol creatinine [33]
3-Methylglutaconic aciduria (Type I) Urine Children (1–13) 200.0 150.0–250.0 μmol/mmol creatinine [33]
Eosinophilic esophagitis Urine Children (1–13) 247.4 0–699.4 μmol/mmol creatinine [33]
Gastroesophageal reflux disease Urine Children (1–13) 119.8 5.5–234.0 μmol/mmol creatinine [33]
HMG-CoA lyase deficiency Urine Children (1–13) 2030.0 60.0–4000.0 μmol/mmol creatinine [33]
MC-CoA carboxylase deficiency Urine Children (1–13) 30350.0 1700.0–59000.0 μmol/mmol creatinine [33]

Notes[edit]

  1. ^ The effect of HMB on skeletal muscle damage has been assessed in studies using four different biomarkers of muscle damage or protein breakdown: serum creatine kinase, serum lactate dehydrogenase, urinary urea nitrogen, and urinary 3-methylhistidine.[1][4][16] When exercise intensity and volume are sufficient to cause skeletal muscle damage, such as during long-distance running or progressive overload, HMB supplementation has been demonstrated to attenuate the rise in these biomarkers by 20–60%.[1][4]
  2. ^ Approximately equal doses of HMB-FA (2.42 grams) and leucine (3.42 grams) do not produce statistically distinguishable anabolic effects as measured by the synthesis of myofibrillar proteins in the skeletal muscle of living humans.[17][18] At 150 minutes post-ingestion, these doses of HMB-FA and leucine increased muscle protein synthesis by ∼70% and ∼110% respectively in one study.[17][18]
  3. ^ At 150 minutes post-ingestion, a 2.42 gram dose of HMB-FA decreased skeletal muscle protein breakdown in living humans by 57% in one study.[17][18] The effect of leucine on muscle protein breakdown is entirely dependent upon insulin secretion and consequently was not measured in the same study.[17] By comparison, the insulin-dependent reduction in muscle protein breakdown following an entire meal that contains leucine and carbohydrates is ~50% on average.[17]
  4. ^ In one study, ingestion of a 1 gram dose of HMB-Ca by healthy volunteers produced a peak plasma HMB level of 120 nmol/ml at 2 hours following ingestion, while ingestion of a 3 gram dose of HMB-Ca produced a peak plasma HMB level of 487 nmol/ml at 1 hour following ingestion.[1]
  5. ^ In one study, consumption of 3 grams of HMB-Ca with 75 grams of glucose resulted in a lower peak plasma HMB level of 352 nmol/ml which occurred later at 2 hours following ingestion.[1]
  6. ^ In one study, ingestion of a 1 gram and 3 gram HMB dose resulted in the excretion of 14% and 28% of the dose as HMB in urine, respectively.[1]
  7. ^ A indicates that the medical condition is a metabolic disorder.

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports. Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455. 
  2. ^ a b c d e f g h i j k l m n o p q r Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Mol. Aspects Med. doi:10.1016/j.mam.2016.04.006. PMID 27106402. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. ... 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013). 
  3. ^ a b c d e f g h i j k l m n o Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97]. 
  4. ^ a b c d e f g h i j k Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Arch. Gerontol. Geriatr. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. 
  5. ^ Portal S, Eliakim A, Nemet D, Halevy O, Zadik Z (July 2010). "Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices". J. Pediatr. Endocrinol. Metab. 23 (7): 641–650. doi:10.1515/jpem.2010.23.7.641. PMID 20857835. 
  6. ^ a b c d e f Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). "Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials". Amino Acids 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID 24057808. 
  7. ^ a b c d Ehling S, Reddy TM (September 2015). "Direct Analysis of Leucine and Its Metabolites β-Hydroxy-β-methylbutyric Acid, α-Ketoisocaproic Acid, and α-Hydroxyisocaproic Acid in Human Breast Milk by Liquid Chromatography-Mass Spectrometry". J. Agric. Food Chem. 63 (34): 7567–7573. doi:10.1021/acs.jafc.5b02563. PMID 26271627. 
  8. ^ Wilson GJ, Wilson JM, Manninen AH (2008). "Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review.". Nutrition & Metabolism 5: 1. doi:10.1186/1743-7075-5-1. PMC 2245953. PMID 18173841. 
  9. ^ a b c Ehling S, Reddy TM (February 2014). "Investigation of the presence of β-hydroxy-β-methylbutyric acid and α-hydroxyisocaproic acid in bovine whole milk and fermented dairy products by a validated liquid chromatography-mass spectrometry method". J. Agric. Food Chem. 62 (7): 1506–1511. doi:10.1021/jf500026s. PMID 24495238. 
  10. ^ a b c d e Fuller JC, Sharp RL, Angus HF, Khoo PY, Rathmacher JA (November 2015). "Comparison of availability and plasma clearance rates of β-hydroxy-β-methylbutyrate delivery in the free acid and calcium salt forms". Br. J. Nutr. 114 (9): 1403–1409. doi:10.1017/S0007114515003050. PMID 26373270. Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB. ... In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form. 
  11. ^ The NCAA Research Staff (January 2006). "NCAA Study of Substance Use Habits of College Student-Athletes" (PDF). National Collegiate Athletic Association. p. 7. Retrieved 24 June 2016. 
  12. ^ a b c d Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ (January 2016). "Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise". Acta. Physiol. (Oxf.) 216 (1): 15–41. doi:10.1111/apha.12532. PMC 4843955. PMID 26010896.  Cite error: Invalid <ref> tag; name "Skeletal_muscle_homeostasis_2016_review" defined multiple times with different content (see the help page).
  13. ^ Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutr. Clin. Pract. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486. There are a number of nutrition products on the market that are touted to improve sports performance. HMB appears to be the most promising and to have clinical applications to improve muscle mass and function. Continued research using this nutraceutical to prevent and/or improve malnutrition in the setting of muscle wasting is warranted. 
  14. ^ Kim JS, Khamoui AV, Jo E, Park BS, Lee WJ (October 2013). "β-Hydroxy-β-methylbutyrate as a countermeasure for cancer cachexia: a cellular and molecular rationale". Anticancer Agents Med. Chem. 13 (8): 1188–1196. doi:10.2174/18715206113139990321. PMID 23919746. 
  15. ^ a b c d Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Crit. Rev. Food Sci. Nutr. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass. ... HMB is converted to HMB-CoA which is then used for the synthesis of cholesterol in muscle cells (Nissen and Abumrad, 1997). Cholesterol is needed for the growth, repair, and stabilization of cellular membranes during exercise (Chen, 1984). ... The meta analysis studies and the individual studies conducted support the use of HMB as an effective aid to increase body strength, body composition, and to prevent muscle damage during resistance training. 
  16. ^ a b c d e f g h i j k l Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). J. Physiol. (Lond.) 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. Retrieved 27 May 2016. Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ∼50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml−1) while continuously infusing AAs (18 g h−1) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008). 
  17. ^ a b c Phillips SM (July 2015). "Nutritional supplements in support of resistance exercise to counter age-related sarcopenia". Adv. Nutr. 6 (4): 452–460. doi:10.3945/an.115.008367. PMID 26178029. 
  18. ^ a b c Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). "Dietary supplementation of β-hydroxy-β-methylbutyrate in animals – a review". J Anim Physiol Anim Nutr (Berl) 99 (3): 405–417. doi:10.1111/jpn.12234. PMID 25099672. Retrieved 1 June 2016. Cholesterol is a major component of the cell membrane, and sarcolemma is the one that relies mainly on de novo synthesis of cholesterol. This is important under stressful conditions when muscle cells may lack the capacity to produce adequate amounts of the cholesterol that is essential to proper functioning of cell membranes. Many biochemical studies have shown that HMB may be a precursor of cholesterol synthesis (Bachhawat et al., 1955; Bloch et al., 1954; Coon et al., 1955; Adamson and Greenberg, 1955; Gey et al., 1957). According to pertinent literature, HMB carbon is incorporated into cholesterol. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the cholesterol synthesis that is needed to form and stabilize the sarcolemma. ... In theory, HMB use as a precursor to cholesterol could aid in stabilizing muscle cell membranes; however, this has not been confirmed by research studies. 
  19. ^ a b c Kornasio R, Riederer I, Butler-Browne G, Mouly V, Uni Z, Halevy O (May 2009). "Beta-hydroxy-beta-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation and survival via the MAPK/ERK and PI3K/Akt pathways". Biochim. Biophys. Acta 1793 (5): 755–763. doi:10.1016/j.bbamcr.2008.12.017. PMID 19211028. 
  20. ^ Salto R, Vílchez JD, Girón MD, Cabrera E, Campos N, Manzano M, Rueda R, López-Pedrosa JM (August 2015). "β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells". PLoS ONE 10 (8): e0135614. doi:10.1371/journal.pone.0135614. PMC 4534402. PMID 26267903. In conclusion, we have shown for the first time that HMB promoted neurite outgrowth through PI3K/Akt and ERK1/2 signaling pathways in Neuro2a cells. Its effect in neuron differentiation is concomitant with higher levels of glucose transporters, the activation of mTOR by mTORC2 and consequently an increase in protein synthesis. Moreover, HMB is involved in promoting MEF2 activity and expression of members of this family of transcriptional factors. We believe that HMB may have great potential as [a neurotrophic factor] promoting neuron differentiation and plasticity. Our results indicated a novel effect of HMB on neurite outgrowth and call to further studies to reveal its positive influences on cognitive outcomes. 
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    Figure 8.57: Metabolism of L-leucine
     
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