1.1. Sources and Biosynthesis
HMB is an acronym for HydroxyMethylButyrate, shorthand for β-Hydroxy β-Methylbutyrate. HMB is a naturally occurring metabolite of the amino acid Leucine where leucine converts to its keto analogue (keto-isocaproate or KIC) and then converts to HMB (via the cytosolic enzyme KIC dioxygenase[1]);[2] it should be noted that the mitochondrial version of KIC dioxygenase converts KIC into the CoA derivative of isovaleric acid (β-hydroxyisovalerate).[1]
All endogenous HMB is derived from leucine[2] and HMB production correlates with dietary leucine intake (seems to be first order kinetics for the cytosolic KIC dioxygenase[3][1]) with about 5% of all leucine oxidation in vivo resulting in HMB formation.[2] Although plasma HMB tends to circulate around 1-4µM, it can increase 5-10 fold following a leucine rich meal.[3]
HMB is a metabolite of dietary leucine in the human body, and mediates a variety of leucine's effects. Dietary intake of leucine can increase HMB formation, and approximately 5% of dietary leucine is converted into HMB in the body
1.2. Supplemental Sources
HMB can be supplemented in the form of a monohydrated calcium salt (commonly referred to as calcium HMB) or as a free acid, which is HMB without the calcium salt. The calcium salt has a similar dissociation constant as calcium acetate[4] and has a Tmax in the range of 1-2 hours following ingestion of 1g Ca-HMB, peaking at 487.9+/-19.0nmol/mL (Cmax) with a half-life of 2.5 hours and returning to baseline 9 hours after ingestion, although some HMB may be retained in the body (just not detected in serum; this study noted only 27% was detectable in urine).[5] A later study using 1g calcium HMB noted a Cmax of 131+/-10µmol/L and a return to baseline after 12 hours;[6] the reason for the disceprancy with the same dose is not known.
When comparing the free acid versus the calcium salt (equivalent levels of HMB, so 0.8g free acid versus 1g calcium HMB), the Cmax is higher with the free acid by 76-97% and the Tmax shorter (30 minutes) while the AUC is also increased by 91-97%.[6] When holding the free acid dose sublingually for 15s before swallowing, there do not appear to be any significant differences relative to simply swallowing.[6]
The free acid form appears to be better absorbed and reaches a serum peak level quicker than the calcium salt form of HMB
Usually, when referring to dietary supplementation in athletes, a dose of 3g HMB is used. This is mostly due to it being the most commonly used dose, but limited evidence that compares 3g against higher doses (6g usually) fails to find any significant difference between the two doses.[7]
6g of HMB does not appear to be significantly better than 3g HMB
2.1. Muscle Mass
In regards to animal studies, 460mg/kg HMB daily to middle aged rats appears to be effective in reducing the rate of motor decline and muscular cross-sectional area during the subsequent aging process, but failed to affect lean mass.[8] When this dose is given to female aged rats, the increase in muscle mass and power output seen with exercise is not augmented.[9]
Human studies are somewhat similar, with 2g HMB (combination supplement with 5g L-Arginine and 1.5g L-Lysine) able to improve muscular control and power output over 12 weeks in women (average age 76.7) without affecting lean mass[10] although the former study noted a trend to increase lean mass (and acute tests noted 20% enhanced protein synthesis[10]) with a subsequent study confirming an increase in lean mass, but without improvements in muscle function.[11] One study adding Vitamin D found benefit with both strength and lean mass over the course of a year.[12]
In older adults participating in weight training, supplemental HMB is associated with an increase in lean mass (0.8kg over 8 weeks) without affecting fat mass.[13]
It is possible for supplemental HMB to the diet of elderly persons to attenuate the rate of muscle loss that occurs during the aging process
3Skeletal Muscle and Exercise
3.1. Mechanisms
HMB possesses mitogenic properties as assesssed by quiscient human muscles cells being stimulated to proliferate with HMB incubation, with a peak of efficacy (increasing MyoD) at 50ug/mL in this study and negative effects at 200ug/mL.[14] This direct mitogenic effect has been noted elsewhere,[15][16] and suggests that HMB can induce quiscient (dormant) muscle cells into cell differentiation.
Cellular proliferation has been noted to occur with HMB supplementation which is secondary to the MAPK/ERK pathway, as MEK inhibitors abolish the proliferative effects of HMB in vitro.[14] This pathway is known to be a regulator of muscle cell proliferation[17][18] and appears to mediate HMB-induced cell proliferation.[14]
HMB can induce muscle cell proliferation via the MAPK/ERK pathway, which is one of the molecular targets of HMB supplementation
When looking at molecular pathways, HMB has been found to stimulate muscle protein synthesis via the mTOR pathway[19] downstream of PI3K/Akt[14] and may occur independently of leucine.[20][14] Increased mTOR expression (429.2%) and subsequent phosphorylation of p70S6K have been noted in rats (320mg/kg).[19]
Akt inhibitors have been noted to inhibit the muscle differentiation induced by HMB (suggesting it is vital to signalling)[14] and it has been hypothesized that the Akt signalling pathway mediates muscle cell differentiation[14]
Muscle protein synthesis appears to be mediated via the mTOR pathway (downstream of Akt signalling, the second molecular target of HMB) and subsequent p70S6K phosphorylation.
HMB is implicated in reducing apoptosis (regulated cell death) of myocytes and satellite cells and due to these anti-apoptotic effects it is thought that HMB supplementation may play a role in situations characterized by apoptosis of myocytes (catabolism associated with aging,[21][22] muscular dystrophies,[23][24] and cachexia[25][26]). HMB has been confirmed in vitro to reduce apoptosis via increasing the Bcl-2/Bcl-X to Bax ratio[14] via Akt signalling[27] which results in the antiapoptotic Bcl-2 and Bcl-X sequestering the pro-apoptotic Bax proteins.[28]
Similar to inducing muscle protein synthesis and differentiation, the anti-apoptotic effects of HMB are downstream of Akt signalling.
3.2. Bioenergetics
320mg/kg HMB to rats for 4 weeks appears to enhance the levels of ATP detectable in red and white skeletal muscle (2-fold and 1.2-fold, respectively) and glycogen content (4-fold) which was assocaited with an increase in citrate synthase activity (2-fold) and tetanic force production (16.5-18.2%) but not muscle mass nor twitch force production.[29]
3.3. Power Output
Acute supplementation of 3g HMB has failed to enhance power output when measured for 72 hours after initial testing and supplementation[30] and using the faster absorbed form of HMB as a free acid has simialrly failed.[31]
A small study in which female judo athletes used 3g HMB for 3 days during caloric restriction (to simulate a pre-competition phase) noted that HMB failed to attenuate the decline in VO2 max and hand grip strength seen with caloric restriction.[32]
Prolonged supplementation of HMB has been noted to improve power output by approximately 1.6% after 9 weeks of 3g HMB during a training regimen with notable (9.1%) increases in leg extension strength but none reported in the upper body[33] while other studies in collegaite athletes fail to note any power enhancement with HMB supplementation at 3g over 10 days[34] or 4 weeks.[35]
There is limited evidence to support the idea that HMB improves power output. HMB taken before workouts has failed to reduce soreness enough to promote power output in the 72 hours measured afterwards and taking HMB during your training regimen does not appear to be better than placebo
3.4. Muscle Damage
3g of HMB supplementation (usage of calcium salt or free acid not disclosed) to exercise in untrained males has failed to significantly alter creatine kinase levels although supplementation before exercise appeared to reduce serum LDH.[30] A later study replicating the results but using a free salt form of HMB (absorbed faster[6]) noted that creatine kinase induced by exercise in trained males was reduced (from 329% to 104%) following 3g of free acid HMB.[31]
Muscle damage as assessed by creatine kinase
In studies that assess muscle soreness, 3g of HMB prior to exercise in untrained males has failed to reduce soreness[30] although 3g (of the free acid rather than calcium salt) prior to exercise has improved the percieved ability of athletes to perform workouts in the few days after testing.[31] Doubling the dose to 6g of the calcium salt has failed to cause acute soreness reduction.[36]
Two studies have been conducted on HMB supplementation and recovery. Both used HMB at the dose of 3g calcium salt (with 0.3g KIC) where one found supplementation aided recovery from weightlifting when measured over the three days after exercise[37] whereas the other study using the same dose to promote recovery from downhill running failed to see benefits;[38] this latter study, however, may have used a supplement containing no HMB[39] which could explain the failure.
Mixed evidence as to whether HMB supplementation can reduce muscle soreness, with limited evidence assessing recovery rates suggesting that both HMB free acid and HMB calcium salt may have some benefits
3.5. Muscle Protein Synthesis
One study comparing the effects of 3.42g HMB against the same oral dose of leucine has found that while HMB increased muscle protein synthesis (assessed by phenylalanine tracers incorporated into myocytes) by 70%, leucine increased muscle protein synthesis by 110%.[40]
Appears to be less effective than an equal oral dose of leucine in promoting muscle protein synthesis
Adding 3g of HMB supplementation to the diet of athletes undergoing physical training has been noted to increase muscle mass by 0.2+/-2.2% over 9 weeks, although this study is confounded with an 8% increase in food intake (and 10% reduction in placebo)[33] and this study is met with two in untrained persons which note that HMB induces muscle protein synthesis in both high (175g) and low (117g) protein groups[3] and that there are no differences due to gender or training status.[41] The one study conducted in young athletes has also reported beneficial results, but the composition of the diet was not disclosed (just a statement that it did not differ).[42]
Conversely, a comparative study between 3g HMB of a time release formulation or standard calcium salt failed to find an effect over 6 weeks on either group[43] and doubling the dose to 6g of calcium-HMB (delivered via protein shake) has failed to outperform placebo (similar protein shake without HMB) over 28 days.[44] Null results have been reported in untrained persons as well,[45] supporting the notion that training status is irrelevant.
There is weak evidence to support the idea that HMB supplementation promotes muscle protein synthesis in trained athletes at 3g daily, and there is likely no benefit
3.6. Muscle Atrophy/Catabolism
HMB possesses an anti-catabolic effect (preserves muscle mass) which is thought to be somewhat novel when compared to Leucine supplementation, as the suppressive effects of leucine on muscle mass are maximal at 5–10mM[46] (markedly higher than fasting levels of 0.1mM[47][48] and postprandial concentrations which have been noted to be about doubled after infusions of 162-261mg/kg/h[49]) despite the attainable concentrations achievable with leucine being sufficient to promote muscle protein synthesis[50] (to a degree greater than HMB[40]) yet 0.5mM leucine appears to have poor anticatabolic effects (6.7% in this animal model that noted a 36-38% enhancement of synthesis[51]). It is possible that HMB serves a role as an anti-catabolic agent despite its lacklustre effect on muscle protein synthesis, and this is somewhat supported by leucine's anticatabolic effects being 10-20 times higher than the concentration required to promote muscle protein synthesis[46] and about 5% of leucine being converted to HMB in the body.[2]
It is plausible that HMB is the anticatabolic metabolite of leucine, whereas it alone is unable to surpass leucine in muscle protein synthesis (perhaps due to other metabolites of leucine being more potent at inducing protein synthesis) but can possibly have a role in preventing muscle loss which does not require the other metabolites of leucine nor leucine itself
At 50μM, HMB has been noted to reduce basal atrogin-1 in vitro as well as the induction of atrogin-1 by catabolic stimuli,[52] which appears to be an attainable concentrations of HMB that is associated with an increase in muscle protein synthesis.[25][14] This suggests that the anti-catabolic effects of HMB are relevant (as atrogin-1 is a protein that mediates muscle protein breakdown[53]) and although they are partly downstream of mTOR signalling[25] they are fully dependent on p38/MAPK activation (p42/44 MAPK appears to be uninvolved).[54][52]
Anticatabolic effects (in vitro) have been confirmed against glucocorticoids,[52] by the proinflammatory stimuli LPS[54][20] and TNF-α,[55][20] and Angiotension II.[55][20]
In vitro research supports the idea of HMB as being anti-catabolic, and this anticatabolic effect appears to extend to a wide variety of catabolic stressors and occurs at a concentration that is attainable following oral ingestion of HMB supplements. This occurs via p38/MAPK signalling
This is noted with 3g of HMB salts over 10 days in older adults undergoing bed rest reversing the decline in lean mass (2.05+/-0.66kg) to no significant change (0.17+/-0.19kg trending to increase);[56] which is similar to branched chain amino acids and isolated leucine.[57][58] Other studies have noted that HMB supplementation is effective in attenuating the rate of lean mass loss seen in cancer cachexia[59][60][26] and a combination of HMB with both L-Arginine and L-Glutamine has shown efficacy in AIDS patients[61] although in vitro they do not appear to be synergistically anti-catabolic.[25] Currently, the anticatabolic effects of leucine and HMB have not been directly compared.
One acute study using 3.42g HMB versus 3.42g leucine noted that while leucine outperformed HMB on muscle protein synthesis, HMB was capable of attenuating muscle protein breakdown (57%).[40]
Studies in athletes designed to assess muscle protein breakdown are limited, with one study using 3g HMB as calcium salt for 3 days in elite female judo athletes during severe caloric restriction (20kcal/kg and 1.33g/kg protein; to simulate before a contest) failing to outperform placebo.[32]
HMB supplementation has been confirmed to be anticatabolic in periods of high risk muscular wasting (cancer cachexia, AIDS, bedrest) at a feasible supplemental dosage, but there is insufficient evidence to properly assess their role in athletes. It appears to be better than leucine at this job, but requires more robust evidence to confirm
4.1. Appetite
There are a few studies administering HMB at 3g to resistance trained males that report changes in dietary intake, such as 9 weeks of supplementation causing a trend to increase overall caloric intake and significant increases in fat intake (total, saturated, and monounsaturated by 44%, 44%, and 53% relative to baseline)[33] and elsewhere HMB supplemented groups have been noted to consume more protein than placebo (this study noting a decrease from baseline in placebo that was not present in HMB);[44] this latter study failed to find differences in fat intake but noted a relative increase in caloric intake.[44]
Other studies have failed to note any significant differences in dietary composition or quantity with 3g HMB in a similar demographic[34] and youth.[42] Some null results have used dietary intervention (either standardizing diet or introducing caloric supplements, which controls for appetite).[43]
Some human interventions note that groups supplemented with HMB at 3g tend to eat more, although this increase in food intake is unreliable in how frequently it occurs and what macronutrients are overconsumed. It is unsure if HMB has a causative role here
4.2. Interventions
Fat mass has been noted to be reduced following ingestion of HMB at 3g to the magnitude of 9+/-14% over 9 weeks, which is somewhat notable despite the variance as the HMB condition was noted to increase food intake by 8% (placebo down 10%).[33] This study is contrasted by one using 3g HMB over 6 weeks failing to find a reduction in fat mass[43]
One study on elite female judo athletes undergoing controlled caloric restriction (20kcal/kg daily, 1.33g/kg protein), 3g of HMB for 3 days noted that only the HMB condition experienced a significant reduction in body fat percentage (from 20.23% to 19.38%; control increased by 0.2%) while no significant differences were observed in the loss of lean mass.[32]
Mixed evidence as to how HMB influences fat loss, but the studies are heterogeneous. It is possible HMB reduces fat mass when paired with severe caloric restriction but when taken daily as part of a standard diet it is ineffective
One study in older adults that failed to find a reduction in fat mass noted that, when assessing volume, there appeared to be a reduction in the area of body fat.[13]
5Interactions with Glucose Metabolism
5.1. Insulin
Insulin has been noted to be acutely induced by HMB supplementation, although it appears to be disconnect from a large reduction in blood glucose (this study noting that 320mg/kg cause a 245% increased in insulin with a 6% reduction of glucose[19]) and its receptor's expression increased but only in liver tissue (not in skeletal muscle).[19]
Similar to leucine, HMB supplementation may cause acute increases in insulin release from the pancreas
5.2. Interventions
In elite female judo athletes, 3g of HMB for 3 days was associated with a drop in fasting blood sugar by 4.6% (from 4.38 to 4.14mM), this study also noted increases in BUN and cholesterol but this may have been due to significant differences at baseline.[32]
6Immunology and Inflammation
6.1. Interventions
A 7 week study in young volleyball athletes given 3g HMB and compared to their teammates given placebo failed to find differences in circulating IL-6 levels after the study period.[42]
7Interactions with Hormones
7.1. Testosterone
A study conducted in elite volleyball athletes (youth) failed to find differences in testosterone after supplementation of 3g HMB over a 7 week period in conjunction with training.[42]
7.2. Cortisol
A study conducted in elite volleyball athletes (youth) failed to find differences in cortisol after supplementation of 3g HMB over a 7 week period in conjunction with training.[42]
7.3. Growth Hormone
A study conducted in elite volleyball athletes (youth) failed to find differences in growth hormone after supplementation of 3g HMB over a 7 week period in conjunction with training.[42]
8Nutrient-Nutrient Interactions
8.1. Creatine
In untrained populations, supplementation of HMB (3g), Creatine (20g for 7 days, 10g for rest of study), or its combination for three weeks noted that creatine was thrice as effective as HMB in increasing lean mass beyond placebo, and that the benefits of creatine and HMB were additive when combined.[62]
One study has been conducted pairing HMB with Creatine in trained rugby athletes using 3g HMB with 6g Creatine Monohydrate for 6 weeks, but the results of the combination group failed to be significantly different than either 3g HMB or the control group.[63] These null results were observed in highly trained athletes previously by the same research group with half the dose of creatine over the same time period of 6 weeks.[64]
9.1. General
Toxicology testing has noted that the No Observed Adverse Effect Level (NOAEL; the highest dose not associated with any toxic signs) for HMB oral ingestion in rats is 3490mg/kg for male rats and 4160mg/kg for female rats;[65] this is an estimated human equivalent[66] of 558mg/kg and 665mg/kg, and assuming a body weight of 150lbs equates to 38g (males) and 45g (females). Other animal toxicology testing includes approximately 5g/kg in pigs over 4 days which failed to alter any biochemical parameter or organ weight (Nutritional role of the leucine metabolite B-hydroxy B-methylbutyrate (HMB) 1997; cited via review[67])
Human toxicological studies have noted that approximately 6g HMB daily (78mg/kg) for one month in untrained young males subject to exercise did not show any toxic effects on serum parameters (half the dose had a spontaneous increase in basophils, considered to be insignificant)[68] and 3g of HMB daily for up to 8 weeks in both youth and older persons has similarly failed to alter toxicological parameters in serum[69] and this dose has been safe for one year of administration (study confounded with L-lysine and L-Arginine ingestion).[11] Overall, standard doses of HMB appear to be well tolerated over long periods of time (meta-analysis).[70]
HMB supplementation at up to 3g daily has been demonstrated to be very well tolerated, and it is suspected that higher doses are equally safe (but with less human testing). There is not too much safety concern with supplemental HMB
