What is HMB

HMB is short for beta-hydroxy-beta-methylbutyrate (ß-hydroxy ß-methylbutyrate) and HMB FA is the free acid form of beta-hydroxy-beta-methylbutyrate. The International Society of Sports Nutrition ¹ has concluded the following.

1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations.
2. If consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout.
3. HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout.
4. 38 mg/kg body weight daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized.
5. Currently, two forms of HMB have been used:
   • Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA may increase plasma absorption and retention of HMB to a greater extent than HMB-CA. However, research with HMB-FA is in its infancy, and there is not enough research to support whether one form is superior.
6. HMB has been demonstrated to increase lean body mass and functionality in elderly, sedentary populations.
7. HMB ingestion in conjunction with a structured exercise program may result in greater declines in fat mass.
8. HMB’s mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively.
9. Chronic consumption of HMB is safe in both young and old populations.

HMB a leucine metabolite, has long been supplemented as a Ca salt (Ca-HMB) to increase strength and performance gains with exercise and to reduce recovery time ². Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). Current evidence suggests that HMB-FA (the free acid form of β-hydroxy-β-methylbutyrate) acts by speeding regenerative capacity of skeletal muscle after high-intensity or prolonged exercise ³. This study ³ investigated the effects of 12 weeks of HMB-FA (3 g) and ATP (400 mg) administration on lean body mass, strength, and power in trained individuals. A 3-phase double-blind, placebo-, and diet-controlled study was conducted. Phases consisted of an 8-week periodized resistance training program (phase 1), followed by a 2-week overreaching cycle (phase 2), and a 2-week taper (phase 3). Lean body mass was increased by a combination of HMB-FA/ATP by 12.7%. In a similar fashion, strength gains after training were increased in HMB-FA/ATP-supplemented subjects by 23.5%. Vertical jump and Wingate power were increased in the HMB-FA/ATP-supplemented group compared with the placebo-supplemented group, and the 12-week increases were 21.5 and 23.7%, respectively. During the overreaching cycle, strength and power declined in the placebo group (4.3-5.7%), whereas supplementation with HMB-FA/ATP resulted in continued strength gains (1.3%). In conclusion, HMB-FA and ATP in combination with resistance exercise training enhanced lean body mass, power, and strength ³. In addition, HMB-FA plus ATP blunted the typical response to overreaching, resulting in a further increase in strength during that period ³. It seems that the combination of HMB-FA/ATP could benefit those who continuously train at high levels such as elite athletes or military personnel ³.

HMB metabolism

HMB is naturally produced in animals and humans from the amino acid leucine ⁴. The first step in production of HMB is the reversible transamination of leucine to α-keto-isocaproate (KIC) by the enzyme branched chain amino acid transferase ⁵ (Figure 1). After leucine is metabolized to α-keto-isocaproate (KIC), KIC is either metabolized into isovaleryl-CoA by the enzymeα-ketoacid dehydrogenase in the mitochondria, or into HMB in the cytosol, by the enzymeα-ketoisocaproate dioxygenase ⁵. α-keto-isocaproate (KIC) is primarily metabolized into isovaleryl-CoA, with only approximately 5% of leucine being converted into HMB ⁵. To put this into perspective, an individual would need to consume over 600 g of high quality protein to obtain the amount of leucine (60 grams) necessary to produce the typical 3 g daily dosage of HMB used in human studies ⁶. Since consumption of this amount of protein is impractical, HMB is typically increased via dietary supplementation.

Figure 1. HMB metabolism

HMB proposed mechanisms of action

Skeletal muscle protein turnover is the product of skeletal muscle protein synthesis and skeletal muscle protein degradation ⁷. When protein synthesis exceeds protein degradation, there is a net synthesis of skeletal muscle protein. However, when protein degradation exceeds protein synthesis, there is a net breakdown of skeletal muscle protein. HMB has been shown to affect both protein synthesis and degradation pathways in skeletal muscle and the effect of HMB on these pathways is summarized below and in Figure ​2.

HMB has been shown to stimulate protein synthesis in skeletal muscle ⁸. This has been hypothesized to occur through stimulation of mTOR, a protein kinase responsive to mechanical, hormonal, and nutritional stimuli. Mammalian target of rapamycin has a central role in the control of cell growth, primarily by controlling mRNA translation efficiency ⁹. Indeed, previous studies have observed that HMB supplementation increases phosphorylation of mTOR and its downstream targets ribosomal protein S6 kinase (S6K) and eukaryotic initiation factor-4 binding protein-1 (4EBP1) ¹⁰.

The growth hormone and insulin-like growth factor 1 (IGF-1) axis may also play a key role in the stimulation of protein synthesis, and it is possible HMB may stimulate protein synthesis through changes in the activity of growth hormone/ insulin-like growth factor 1 (IGF-1) axis. Gerlinger-Romero et al. ¹¹ observed an increase in pituitary growth hormone mRNA and protein expression after one month of HMB supplementation. Moreover, liver IGF-1 mRNA and serum IGF protein levels were also increased in the HMB-supplemented rats; however, this occurred without an increase in skeletal muscle IGF-1. In contrast, an increase in skeletal muscle insulin-like growth factor-1 (IGF-1) has been observed after HMB treatment of chicken and human myoblasts ¹². Taken together, these results suggest that HMB may affect growth hormone/IGF-1 axis signaling; however, the effect on skeletal muscle protein synthesis requires more investigation. It is possible that the growth hormone/IGF-1 axis signaling may require a large change in plasma HMB levels. At this point, it is not clear whether a threshold response to a specific concentration of plasma HMB exists. This certainly merits further investigation.

In addition to the direct effects on protein synthesis, HMB has been shown to affect satellite cells in skeletal muscle. Kornaiso et al. ¹² cultured myoblasts in a serum-starved state to induce apoptosis. When myoblasts were cultured with HMB, the mRNA expression of myogenic regulatory factor D (MyoD), a marker of cell proliferation, was increased in a dose responsive manner. Moreover, the addition of various concentrations of HMB (25–100 μg/ml) to the culture medium for 24 hours resulted in a marked increase of myogenin and myocyte enhancer factor-2 (MEF2) expression, markers of cell differentiation. As a result, there was a significant increase in the number of cells, suggesting a direct action of HMB upon the proliferation and differentiation of myoblasts.

Summary of HMB proposed mechanisms of action

HMB has been shown to result in a net positive balance of skeletal muscle protein turnover though stimulation of protein synthesis and attenuation of protein degradation. HMB induces protein synthesis through up-regulation of the mTOR pathway while HMB attenuates protein degradation through attenuation of the ubiquitin-proteasome pathway and caspase activity. Moreover, HMB stimulates skeletal muscle satellite cell activation and potentially increases skeletal muscle regenerative capacity.

Figure 2. HMB proposed mechanisms of action

[Source ¹³]

Best HMB supplement

The benefits with HMB to improve muscle performance with vigorous exercise have generally been achieved with the Ca salt of HMB (HMB Ca) administered in capsule form. However, as shown in previous studies, and confirmed by the findings of these studies ¹⁴, ¹⁵, peak plasma levels of HMB are not reached until approximately 120 min after ingestion of Ca-HMB, which makes it inconvenient for scheduling exercise sessions to coincide with peak plasma HMB levels. This study ² was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB (HMB calcium salt). The pharmacokinetics of each form when administered mixed in water. Ten human subjects (five male and five female) were studied in a randomized crossover design. There was no significant sex by treatment interaction for any of the pharmacokinetic parameters measured. HMB-FA administered in capsules was more efficient than Ca-HMB capsule at HMB delivery with a 37 % increase in plasma clearance rate (74·8 v. 54·5 ml/min) and a 76 % increase in peak plasma HMB concentration (270·2 v. 153·9 μmol/l), which was reached in one-third the time ². When HMB-FA and Ca-HMB were administered in water, the differences still favored HMB-FA, albeit to a lesser degree. Plasma HMB with HMB-FA administered in water was greater during the early phase of absorption (up to 45 min post administration); this resulted in increased during the first 60 minutes after administration, when compared with Ca-HMB mixed in water. In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form ². This study showed that the time to peak HMB level decreased by two-thirds when HMB was delivered as the free acid in capsule form (HMB-FA), thus making it more convenient to time peak HMB level with exercise ². Is is hypothesized that HMB as HMB-FA would offer a more convenient delivery form resulting in an improved anabolic effect of HMB on muscle protein synthesis and diminishing protein breakdown.

In conjunction with resistance training, HMB-FA supplementation may attenuate markers of muscle damage, augment acute immune and endocrine responses, and enhance training-induced muscle mass and strength ¹⁶. HMB-FA supplementation may also improve markers of aerobic fitness when combined with high-intensity interval training. Nevertheless, more studies are needed to determine the overall efficacy of HMB-FA supplementation as an ergogenic aid (performance enhancing properties).

Does HMB work?

In 1996, Nissen et al. ¹⁷ first demonstrated that supplementation with HMB lowered muscle proteolysis following resistance training, and augmented gains in lean body mass and strength in a dose-dependent manner. Since that time HMB has been studied in a variety of anaerobic and aerobic training conditions ¹⁸. While numerous studies have supported the efficacy of HMB supplementation for enhancing recovery ¹⁹, lean body mass ²⁰, strength ¹⁷, power ²¹, and aerobic performance ²², there have been conflicting results ¹. HMB has a long history of use as a nutritional supplement for enhancing recovery, and for increasing strength, power, aerobic performance and lean body mass with exercise ²³. HMB improves muscle protein balance by decreasing muscle protein breakdown and by increasing muscle protein synthesis ²⁴, resulting in reduced muscle damage and faster and improved recovery ²⁵.

The anabolic stimulus of exercise results in an increase in muscle protein synthesis in as little as 1 hour post exercise ²⁶, and it can persist for up to 48 hours post exercise ²⁷. These anabolic events are also accompanied by depletion of muscle energy stores in the form of glycogen, resulting in decreased exercise intensity, and associated with increased muscle damage ²⁸. The changes have been attributed to increased skeletal muscle AMP-activated protein kinase activity and reduced phosphorylation of 4E-BP1 in the mTOR pathway, as occurs with resistance exercise ²⁶. HMB supplementation has been shown to increase phosphorylation of 4E-BP1 in human muscle ²⁴.

Other metabolic effects of HMB have been demonstrated in animal models. Turkeys fed HMB during the last 15 weeks of rearing had increased bone density and strength and an increase in some plasma amino acids including the branched-chain amino acids ²⁹. Tatara et al. ³⁰ also demonstrated increased growth and bone density, and increased growth hormone and insulin-like growth factor-1 (IGF-1), in offspring of sows fed HMB for the final 2 weeks of pregnancy; increased bone density and plasma amino acid concentrations in pigs with fundectomy-induced osteopenia ³¹; and improved somatotrophic and accelerated bone metabolism in lambs fed HMB for the first 21 days after birth ³². The improvement in somatotrophic axis function was further demonstrated in rats when chronic HMB administration was shown to stimulate the growth hormone/insulin-like growth factor-1 axis ³³. Recently, HMB supplementation was shown to enhance the exercise-stimulated increase in growth hormone and IGF-1 response in humans, similar to what the previous studies in animals had demonstrated ³⁴.

The effects of HMB supplementation on skeletal muscle hypertrophy in healthy untrained and trained adults

HMB’s effects on skeletal muscle mass, strength, and hypertrophy have been studied in exercising humans for nearly two decades ¹⁷. Similar to its reported effects on skeletal muscle damage, a wide range of subject populations (untrained vs. resistance trained; male vs. female) and training protocols (Table 1) have been examined. Training protocols have varied in duration (10 days to 12 weeks) ²¹, periodization scheme, and training modalities (machines and free weights vs. free weights only). To confound the situation further, some researchers have designed and monitored the resistance-training protocol, while others have left it up to subjects to train on their own. In other cases, subjects have participated in unspecified training protocols reportedly provided by various team coaches or training camps. In addition, studies have provided a variety HMB doses ranging from 1.5 to 6 g daily. Moreover, some studies have supplemented HMB along with creatine monohydrate ¹⁹ or arginine and glutamine ²¹. Further, some researchers have controlled for diet ²¹, while the majority have not. Lastly, the outcome measures for indices of skeletal muscle mass have varied from less accurate indirect indices (skin fold and bioelectrical impedance measures), to dual x-ray absorptiometry (DXA) ²¹ to determine fat free mass (FFM) and lean body mass (LBM), respectively. Thus, in order to make any overall conclusions on HMB’s effectiveness, the validity and reliability of each of these measures needs to be considered.

Table 1. HMB effects on body composition and performance

Experiment	Subjects	Protocol	Periodized	Diet control	Duration/dose	Additional supplements	Body composition measures	Performance measures	Outcomes of HMB–Ca supplementation relative to placebo
Nissen 1996 17	Trained, NCAA football players	Monitored progressive resistance training	No	No	7 weeks, 3 grams per day HMB-Ca	No	TOBEC for total FFM and FM	Bench Press and Squat	FFM: + 1.9 % FM: – 0.5 % Strength: + 2.3 % average
Nissen 1996 17	Untrained college-aged males	Monitored progressive resistance training	No	Yes	3 weeks, 1.5 or 3 grams per day HMB-Ca	No	TOBEC for total FFM and FM	Strength: Average weight lifted during last 3 working sets of upper and lower body exercises	FFM: + 0.6 % FM: No Effect Strength: +2.6 to 17.4 % depending on lift
Jowko 2001 35	Active, college-aged males	Monitored progressive resistance training	No	No	3 weeks, 3 grams per day HMB-Ca	20 grams creatine per day for 7 days followed by 10 grams per day for 14 days	BIA	Strength: Cumulative 1-RM of major lifts (Squat, Bench Press, Clean)	FFM: + 0.6 % FM: – 0.7 % Strength: + 9 %
Kreider 1999 36	Resistance trained, college-aged males males with > 1 year experience	Not monitored: Instructed not to change current individualized training regimens	No	No	28 days, 3 or 6 grams per day HMB-Ca	No	DXA for: LBM and FM	Strength: Bench Press and Leg Press	LBM: No Effect FM: No Effect Strength: No Effect
Gallagher 2000 20	Untrained college-aged males	Monitored progressive resistance training	No	No	8 weeks, 3 or 6 grams per day HMB-Ca	No	7 site Skin Fold	Isometric and Isokinetic testing, Non-specific to training stimulus	FFM: + 3 % FM: – 1.6 % Strength: +2-3.5 % No differences between 3 and 6 g
Panton 2000 37	Men and women, divided into untrained and resistance trained (> 6 months), 20–40 yrs of age	Monitored high intensity progressive resistance training	No	No	4 weeks, 3 grams per day HMB-Ca	No	Underwater Weighing	Bench Press and Leg Press 1-RM	FFM: +.5 kg FM: – .6 % Strength: +3-15 %
Hoffman 2004 38	College Football players	Football camp, not controlled by investigators	No	No	10 days, 3 grams per day HMB-Ca	No	Not Measured	Wingate Power	No Effects
Kraemer 2009 21	Recreationally active, college-aged males	periodized resistance training split	Yes	Yes	12 weeks, 3 grams per day HMB-Ca	14 grams arginine and 14 grams glutamine per day	DXA for LBM and FM and Limb Circumference	Squat and Bench Press 1RM Vertical Jump	LBM: + 40% FM: -40 % Strength: 50 % Power: +85 %
Thomson 2009 39	Trained college-aged males	Non Monitored Assigned progressive resistance training program with 84 % compliance	No	No	9 weeks, 3 grams per day HMB-Ca	No	BIA	Bench Press, Preacher Curl, and Leg Extension 1-RM	FFM: 0.4 FM: – 3.8 Strength: 1.1-9.0 depending on lift
Portal 2011 40	Elite adolescent volleyball players 13.5-18 yrs of age	Combination of progressive, resistance, and endurance exercise	Not reported	No	7 weeks, 3 grams per day HMB-Ca	No	DXA	Power on Wingate Strength of Bench Press and Leg Press	Fat: PL = +3.5% Vs. HMB= −6.6% FFM: PL= no change Vs. HMB= +3.7% Power: PL = +3% HMB = +13.5% Strength: PL=0-6.7 % vs. HMB +15.7 % – 23.5 %
Ransone 2003 41	College football players	Progressive resistance and endurance exercise	No	No	4 weeks, 3 grams per day HMB-Ca	No	Skin Folds	Bench Press, Power Cleans, Squats 1-RM	FFM: +0.3 FM: – 3.8 Strength: 1.7 % increase
Kreider 2000 42	Trained, college football players	Offseason strength and conditioning program	Yes	No	4 weeks, 3 grams per day HMB-Ca	No	DXA	Bench Press, Power Cleans, Squats 1-RM, 12×6 second sprint performance	No Effects
O’Connor 2007 43	Trained rugby players, 25 yrs of age	Progressive resistance training	No	No	6 weeks, 3 grams of HMB-Ca or HMB-Ca + Creatine per day	3 grams creatine per day	Skin Folds	Squat, Bench Press, and Deadlift 1-RM Wingate Power	Neither HMB-Ca nor creatine had an effect
Slater 2001 44	College-aged, trained polo players and rowers	Non-controlled workouts assigned by the athletes’ respective coaches	Unknown	No	6 weeks, 3 grams per day HMB-Ca	No	DA	Bench Press, Hip Sled, Pullups 3-RM	No significant effects

Abbreviations: TOBEC = total-body electrical conductivity; DXA = Dual-energy x-ray absorptiometry; BIA = bioelectrical impedance; FFM = fat free mass; FM = fat mass; LBM = lean body mass (TOBEC).

Untrained individuals

In both trained and untrained individuals the majority of studies using HMB have lasted four weeks or less (Table 1). In untrained individuals supplementation with HMB has been demonstrated to increase fat free mass, as well as strength in as little as three weeks ¹⁷. These findings are not surprising if HMB operates through speeding recovery of damaged skeletal muscle tissue ¹⁷. In particular, research indicates that the initial weeks of training result in the highest magnitude of damage in an untrained population (Table ​1). Research supports that rate of improvement in novice lifters decline as their training experience increases ⁴⁵, however, the majority of studies using HMB were not periodized. For these reasons HMB’s magnitude of effect over a placebo in novices only slightly increases when analyzing results over eight weeks versus three to four weeks utilizing a linear resistance training model. Finally, in untrained individuals it appears that 3 g of HMB per day produces greater gains than 1.5 g of HMB per day ¹⁷; though, 6 g of HMB per day was not shown to further increase HMB’s effectiveness over 3 g of HMB per day (Gallagher PM, Carrithers JA, Godard MP, Schulze KE, Trappe SW. Beta-hydroxy-beta-methylbutyrate ingestion, part I: effects on strength and fat free mass. Med Sci Sports Exerc. 2000;32:2109–2115. doi: 10.1097/00005768-200012000-00022()). However, only one study has examined a daily dose of 6 g HMB, therefore no definitive recommendation on (upper limit) dosing can be provided until additional research is conducted.

According to the available science, the effectiveness of HMB appears to be optimized under conditions of continually changing loading patterns. Specifically, Kraemer and colleagues ²¹ had recreationally active, but not resistance-trained, individuals participate in a 12-week, periodized training program. Subjects were randomly assigned to 3 g daily of an HMB-Ca supplement that contained 14 g glutamine and 14 g arginine, or a placebo in a double-blinded manner. The training program consisted of three constantly changing loading patterns targeting a strength, hypertrophy, and strength endurance continuum. Moreover, these researchers controlled for subjects’ diets, and monitored every training session. Results showed that these previously untrained subjects in the HMB-Ca group experienced greater gains in LBM (+ 3.5 kg in placebo vs. + 9 kg HMB-Ca), and squat strength (+29 kg in placebo vs. + 46 kg in HMB-Ca ).

HMB supplementation in youth and adolescent populations

Research in infants using HMB has yet to be done using human models. However, there is recent epigenetic data in animal models to suggest that HMB given during pregnancy can result in prenatal programming of skeletal muscle tissue. Specifically, maternal supplementation of HMB during pregnancy resulted in greater weight and lean mass gain in piglets than those not under maternal treatment ⁴⁶. Moreover, research in growing, pre-adolescent rats suggests that HMB supplementation was able to stimulate skeletal muscle hypertrophy in the extensor digitorum longus and soleus muscles ⁴⁷, and that HMB was able to increase the mTOR and phosphorylation of p70S6K in the extensor digitorum longus muscle ⁴⁷.

There is very little research examining the effects of HMB in human adolescent populations. However, this population may be an ideal model for HMB supplementation as resources required to augment their training adaptations compete with resources needed for normal growth of organs, bones, and muscle tissue ⁴⁸. HMB assists in recovery in challenging situations, and therefore may be beneficial to younger populations. In a recent study the effects of 3 grams per day of HMB-Ca on male and female elite adolescent (13–18 yrs) volleyball players during the first seven weeks of their training season was investigated ⁴⁹. Their results demonstrated that fat free mass increased in the HMB-Ca supplemented group, but not placebo supplemented group. Moreover fat mass declined (−6.6 %) in the HMB-Ca supplemented, but not placebo supplemented group (+3.5 %). In addition, Wingate test peak power, and upper- and lower-body strength were greater with HMB-Ca supplementation. No changes in hormone status (testosterone, cortisol, IGF-1, growth hormone) or inflammatory mediators (IL-6 and IL-1 receptor antagonist) occurred with HMB-Ca supplementation.

HMB supplementation in aging and masters athletes

Skeletal muscle loss is a part of the aging process and approximately 30% of skeletal muscle mass is lost between the 5th and 8th decades of life ⁵⁰. This reduction in skeletal muscle mass occurs for several reasons, including maintaining a sedentary lifestyle, malnutrition, insulin resistance, oxidative stress, and alterations in skeletal muscle metabolism and repair, as reviewed by Kim et al.⁵¹. In addition, the elderly exhibit impaired anabolic and anti-catabolic responsiveness to resistance exercise and amino acid feeding, termed anabolic resistance ⁵². Anabolic resistance can be overcome by supplementation of leucine, and it has been hypothesized that this may be due to the conversion of leucine to HMB ⁴⁷. These data suggest a potential benefit of HMB supplementation in aging individuals ⁵¹.

Studies have investigated the effects of nutritional supplements containing HMB, without an exercise intervention, on skeletal muscle mass in the elderly ⁵³. Flakoll et al. ⁵⁴ investigated the effects of 12 weeks of either HMB, arginine and lysine supplementation or placebo supplementation in 50 elderly subjects and observed an increase in lean body mass, leg strength, handgrip strength, and a decreased “timed up and go” test time in the HMB-supplemented group compared to the placebo-supplemented group. Baier et al. ⁵⁵ investigated the effects of one year of either HMB, arginine, and lysine supplementation or control supplementation in 77 elderly subjects over 65 years of age and observed significant increases in lean mass in the HMB-supplemented group and no change in lean mass in the control-supplemented group. Moreover, an increased rate of protein turnover in the HMB group and a decreased rate of protein turnover in the placebo group were observed after both three and 12 months of supplementation. In addition to the beneficial effects of HMB on skeletal muscle, HMB supplementation may also have effects on body fat. Wilson et al. ⁵⁶ investigated the effects of 16 weeks of HMB supplementation in aged rats and found that body fat mass, as measured by DXA, increased by nearly 50% from young to middle age, and that HMB supplementation prevented this gain in body fat with aging. Moreover, these researchers also found that HMB supplementation was able to prevent the loss of skeletal muscle fiber size in very old as compared to young rats. These studies suggest that HMB alone can decrease body fat and increase skeletal muscle mass and strength in aging populations.

The efficacy of HMB supplementation in conjunction with a strength-training program has also been investigated in aging populations. Vukovich et al. ⁵⁷ compared the effects of eight weeks of either HMB or placebo supplementation on body composition and strength in 70 year old men and women performing a strength training program. A trend towards an increase in lean mass was observed in the HMB-supplemented group, while no change was observed in the placebo-supplemented group. However, it should be noted that body composition was measured with skinfold calipers in this study. The HMB-supplemented group also had an approximate 8% decrease in fat mass. Upper and lower body strength increased by 15-20%; however, there was no difference in strength changes between the groups. While the differences observed were not statistically different with HMB supplementation, it should be noted that the training protocol in this study consisted of 2 sets of 8–12 repetitions 2 days per week. Thus, this particular study suggests that in previously untrained older adults the use of HMB may not provide any further benefit than training alone. Considering the paucity of available research on HMB ingestion and resistance exercise in older adults, additional investigations are warranted.

Trained individuals

The rate of adaptation in strength, power, and hypertrophy in trained and untrained individuals markedly differs. For example Ahahtanin et al. ⁵⁸ found that 21 weeks of resistance training resulted in 21% and 4% increases in strength in untrained and highly strength trained athletes, respectively. In these subjects, HMB appears to augment adaptations following unaccustomed high intensity training protocols. Because the rate of adaptation is markedly slowed in trained populations it is likely that HMB’s effects in this population will be optimized over longer duration protocols (>6 weeks). For example, the majority of studies in trained individuals lasting six weeks or less found little to no significant differences with HMB-Ca compared to a placebo [15,18,19,26]. However, those lasting longer than six weeks generally elicited positive effects in strength, and FFM ³⁹.

The capacity of a training protocol to provide a novel training stimulus may be critical to consider when studying HMB. To date, the majority of studies have been linear in nature, and not monitored by the investigator (Table 1). The first study conducted in trained individuals lasted 28 days, and subjects were instructed to maintain their normal training protocols ⁵⁹. Neither the placebo nor HMB-Ca supplementation resulted in increases in CK or strength, thus suggesting that HMB may not work without a novel training stimulus. Following this study, Slater et al. ⁶⁰ recruited trained water polo and rowing athletes. For this study the training protocol lasted six weeks, and again was not controlled by the investigators; however, the athletes were under the supervision of their respective strength coaches. As such, subdivisions of athletes in this protocol each experienced variable training stimuli making it extremely difficult to determine any direct effects of HMB supplementation. For this reason, no effects of HMB-Ca were noted.

The most recent study using HMB-Ca was conducted by Thomson and colleagues ³⁹. These researchers supplemented individuals with reportedly one year or more of resistance training experience with 3 g of HMB-Ca or a placebo while performing a linear (periodized) resistance-training program. Subjects were asked to follow the program for nine weeks; however, they were not monitored. Subject compliance to the training program was on average 84 ± 22%. These last two points are critical to analyze for two reasons. First, a 20% lack of compliance lowers overall training frequency, which decreases the probability of optimizing HMB’s effects on recovery rate. Second, research demonstrates that directly supervised, heavy-resistance training results in a greater rate and magnitude of training load increases in resistance-trained individuals ⁶¹. Moreover, supervised training results in greater maximal strength gains compared with unsupervised training ⁶². For this reason it is likely that the training stimulus and frequency in this nine week study did not exploit HMB’s capacity to speed recovery under maximal, and constantly varying training stimuli. An additional confounding variable in this study was that skeletal muscle hypertrophy was estimated from bioelectrical impedance, which has been demonstrated to have high variability ⁶³. Finally, the outcome strength measures were single joint movements (e.g., biceps curl and leg extension). If HMB increases overall lean mass, it may have been more appropriate to select multi-joint, structural exercises such as the squat and/or bench press. However, even with these limitations nine weeks of HMB-Ca supplementation resulted in small, but statistically significant decreases in fat mass, and increases in fat free mass and strength.

To date, few studies have examined monitored resistance training in trained athletes. Of these, only one exceeded six weeks in duration. The first was conducted by Kreider et al. ⁴² who examined the effects of four weeks of HMB supplementation during a supervised offseason strength and conditioning program in college football players and observed no changes in lean mass or strength. However, Panton et al. ³⁷, examined the effects of four weeks of HMB supplementation during resistance training in 36 women and 39 men (20–40 yrs) with varying levels of training experience. Their training protocol consisted of very high intensity loads (>80 % 1-RM) which were consistently adjusted as subject tolerance for a given weight increased. Due to the high intensity nature of the protocol, the HMB-Ca group showed greater decreases in body fat compared with placebo supplementation (−1.1 % vs. -0.5%, respectively); increases in bench press strength (7.5 kg vs. 5.2 kg, respectively); and lean body mass (1.4 kg vs.0.9 kg, respectively). These changes were independent of training experience. Moreover, Nissen et al. ¹⁷ conducted a seven week high intensity (>80% 1-RM) training study in individuals who could bench press ≥ 135 kg and squat greater than 1.5 times their bodyweight and found that subjects supplemented with HMB-Ca gained an average of 4.5 kg more on their bench press and 3.2 kg more on their squat when compared to the placebo supplemented subjects.

Collectively the findings presented in Table ​1 lead to the following conclusions:

1. In untrained individuals, HMB can enhance muscle hypertrophy and dynamic strength in as little as three weeks; however,
2. For trained individuals it is important to realize that adaptations occur at a slower rate than in untrained individuals ⁵⁸. For this reason, HMB will likely be most beneficial over longer training durations (> 6 weeks) in trained individuals.

HMB supplementation has been demonstrated to result in modest increases in strength during unsupervised, resistance training programs greater than six weeks in duration. Presently, available literature suggests 38 mg/g body weight per day, divided into two to three servings provides an adequate amount of HMB to enhance adaptive processes in muscle. However this prescription is far from refined, as no research has investigated the optimal dosage of HMB per serving to optimize protein balance. Research has also not focused on the ideal distribution (e.g. number of times HMB should be consumed per day) needed to optimize HMB’s effects. Finally, more research needs to be done comparing HMB-FA to HMB-Ca. Supplementation with HMB-FA has been shown to increase HMB levels to a greater and more rapid peak in blood than supplementation with HMB-Ca. The HMB is also retained to a greater extent as well. It is plausible that these differences may augment the effects of HMB-Fa on overall adaptive processes.

HMB in athletes training in an energy restricted state

The effects of HMB supplementation on regenerative capacity and fat metabolism make it a unique candidate for a number of special situations in which skeletal muscle wasting is indicated. One situation in particular concerns caloric (energy) restriction. Restricting calories prior to competition is commonly used by bodybuilders and those in weight-classified sports. However, research demonstrates that calorie restriction can cause decreases in lean mass and exercise performance ⁶⁴. In a recent study ⁶⁴ on female judo athletes who were calorically restricted for three days, body weight and body fat percentage were significantly decreased in the subjects consuming HMB-Ca compared to the control group. There were also trends for HMB to have positive effects on LBM, which tended to decrease more in the control group (−1.6%) than in the HMB group (−0.5%). Peak power decreased by nearly 11% in the control group compared to only 5% in the HMB group. These findings suggest that individuals who are moderately calorically restricted may augment fat loss and prevent declines in LBM by supplementing with HMB.

HMB dosage and timing

The duration, dosage, and timing of HMB supplementation have notably varied in the literature. The first study to look at the duration and dose of HMB was conducted by Nissen and colleagues ¹⁷. Their results indicated that HMB-Ca attenuated protein breakdown to a greater extent following two weeks of supplementation than following one week, and that HMB-Ca was not able to significantly reduce CK concentrations until the third week of training. These effects appeared to be greater when ingesting 3 g of HMB-CA compared to lower doses of the supplement (1.5 g of HMB-CA). Other investigations who have supplemented with HMB-Ca for two or more weeks have generally reported that the supplement lowers indices of skeletal muscle damage and soreness, while those supplementing for shorter periods of time have not. These findings suggest that HMB-Ca supplementation may be optimized when ingestion begins two weeks prior to the onset of a new training period or change in training workload.

In the majority of studies, however, researchers have had subjects consume HMB-Ca with breakfast, lunch, and dinner, without any regard to how the supplement is timed relative to exercise. Currently only two studies have reported HMB’s acute effects on skeletal muscle damage and recovery. Wilson et al. ⁶⁵ examined the acute and timing effects of an oral 3 g bolus of HMB-Ca supplement on 16 untrained males using a unilateral, isokinetic leg extension based training protocol. These researchers found that HMB-Ca consumed 60 minutes prior to exercise prevented a significant rise in LDH, and tended to decrease soreness of the quadriceps relative to either the HMB-Ca supplement consumed following exercise, or a placebo supplement given prior to exercise.

Collectively these findings suggest the following: HMB supplementation appears to speed recovery in untrained and trained individuals if the exercise stimulus is high intensity, and/or high volume in nature. For untrained individuals this would likely occur with the introduction of most exercise regimens; however, in a trained population the exercise stimulus will likely need to center on free weights and compound movements. In regards to optimizing HMB supplementation, it appears that HMB has both acute and chronic effects. HMB’s acute effects likely depend upon supplementation pre-exercise. If taking HMB-Ca, the recommendation would be to consume 3 g, at least 60 minutes prior to intense exercise. If consumed with glucose it may need to be taken as long as two hours prior to training. HMB in the HMB-FA form may have an overall faster and greater effect based upon the rise in plasma levels. Thus, athletes could consume the supplement in HMB-FA form 30–60 minutes prior to exercise. Finally, in order to optimize HMB’s chronic effects, the recommendation would be to consume 3 g daily, divided into three equal servings for a minimum of two weeks prior to a potentially damaging skeletal muscle event.

Summary

High intensity resistance training is essential for athletes seeking to add strength and hypertrophy. However, high intensity resistance training that results in skeletal muscle damage may take a number of days to recover from; in this case, overall training frequency may be reduced. HMB appears to speed recovery from high intensity exercise. These effects on skeletal muscle damage appear to be reliant on the timing of HMB relative to exercise, the form of HMB, the length of time HMB was supplemented prior to exercise, the dosage taken, as well as the training status of the population of interest. In particular, the supplement should be taken at 1–2 grams 30–60 minutes prior to exercise if consuming HMB-FA, and 60–120 minutes prior to exercise if consuming HMB-Ca. Finally, it is likely that HMB will work ideally if consumed at a dosage of 3 grams for two weeks prior to a high intensity bout that induces muscle damage.

HMB appears to interact with the training protocol utilized, as well as the experience of the athlete. In untrained individuals, low volume, high intensity resistance training will cause enough skeletal muscle tissue disruption to benefit from HMB supplementation. In addition to speeding recovery from high intensity exercise, HMB may assist athletes in preventing loss of lean body mass in catabolic situations such as caloric restriction. HMB may also be beneficial for augmenting body composition and physical performance in master’s level athletes, or aging individuals in general. Finally, although research is limited it appears that the supplement may also enhance aerobic performance.

HMB side effects

The safety of HMB has been widely studied ⁶⁶. In a study conducted in compliance with Food and Drug Administration Good Laboratory Practice, rats consuming a diet of up to 5% HMB-CA for 91 days did not exhibit any adverse effects vis a vis clinical observations, hematology, clinical chemistry or organ weights ⁶⁶. This study reported no observed adverse effect levels (NOAEL) of 3.49 and 4.16 g/kg body weight for male and female rats, respectively ⁶⁶. This would be the equivalent of an 81 kg human male consuming almost 50 g HMB-Ca per day for three months with no adverse effects, based on human equivalent dosing  normalized to body surface area. In humans, consumption of 6 g HMB/day for one month had no effect on cholesterol, hemoglobin, white blood cells, blood glucose, liver or kidney function ⁶⁷. In addition, two meta-analyses, one with HMB supplementation alone and another with HMB supplementation combined with glutamine and arginine, have concluded that HMB is safe and does not result in any adverse effects ⁶⁸, ⁶⁹. Moreover, Baier et al. ⁷⁰ examined the effects of a 2–3 g of a daily ingestion of HMB-Ca in combination with amino acids for one year in the elderly and found that HMB consumption did not result in any changes in blood or urine markers of hepatic or renal function or blood lipids. Although the previous studies found no adverse events associated with HMB supplementation, a recent rodent study found an increase in plasma insulin after 320 mg/kg body weight day supplementation for one month, which showed a significant increase in fasting insulin levels, suggesting a possible decrease in insulin sensitivity ⁷¹. However, this finding has not been reported in any previous human study. Evidence to date indicates that that consumption of HMB is safe in both young and old populations; however, future studies examining the effects of HMB on insulin sensitivity in humans are warranted ¹³.

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