INTRODUCTION
β-Hydroxy β-methylbutyric acid (HMB), or 3-hydroxy-3-methylbutanoic acid (IUPAC), is a metabolite of the essential amino acid Leucine. It has been used as an ergogenic aid among bodybuilders, and to reduce muscle damage in elderly and clinical population, such as patients with cancer, AIDS and COPD.
HMB is a metabolite of the ketogenic amino acid leucine. A small amount (0.3 - 0.4 g/d) of HMB is produced endogenously through leucine metabolism. The first step in leucine oxidation is transamination to ketoisocaproate. The majority (approximately 95%) of ketoisocaproate is metabolized to isovaleryl-coenzyme-A by the mitochondrial enzyme Branched-chain a-keto-acid dehydrogenase, and ultimately enters the citric acid cycle.
However, a small amount of ketoisocaproate (approximately 5%) is converted to HMB by the enzyme a-ketoisocaproate dioxygenase in the cytoplasm. Although HMB can be synthesized endogenously from leucine, approximately 60 g of leucine would need to be consumed daily to reach the HMB dosage of 3 g/d that has been used in most studies. High leucine protein sources (cheese, eggs, meat) contain up to 10% leucine. Therefore, to obtain 60 g of leucine from the diet, one would have to consume at least 600 g of meat daily. Clearly, this level of consumption is not practical, and it would overload the kidneys; therefore, to obtain 3 grams of HMB daily, supplementation appears to be necessary.
PHARMACOKINETICS
Most Authors seem to agree that the optimal dosage of HMB is 3 g/d. Some studies showed that HMB supplementation at 3 g/d in healthy subjects increased strength in a dose-dependent manner, whereas the consumption of a bigger dose up to 6 g/d, did not result in any additional effect. Current evidence suggests that 1 g of HMB should be consumed 3 times per day, for a total of 3 g daily.
After ingestion of 3 g of HMB, plasma HMB peaked one hour after consumption. Approximately 30% of the ingested HMB accumulates in the urine, while 70% is retained in the body.
PARMACODYNAMICS
Muscle tissue mass represents the net balance between muscle protein synthesis and degradation. Numerous studies have investigated the effects of HMB on muscle protein balance. Results of studies using cultured muscle cells have found that HMB decreases muscle protein degradation.
HMB's mechanisms of action are generally considered to operate through its capacity to stabilize the sarcolemma and attenuate proteolytic pathways.
A damaged muscle cell may lack the capacity to produce adequate amounts of cholesterol needed for various cellular functions, including the maintenance of sarcolemmal integrity. The inhibition of cholesterol synthesis results in impaired muscular function, heightened muscular damage, and muscle cell necrosis. In muscle tissue sarcolemmal integrity relies heavily on de novo cholesterol synthesis. Cholesterol is formed from Acetyl-CoA, in which the rate-limiting step is the formation of mevalonic acid, catalyzed by the enzyme HMG CoA reductase. The majority of HMB is converted into HMG-CoA reductase, into a muscle cell. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the synthesis of cholesterol, needed to stabilize the sarcolemma.
The Ubiquitine-proteasome pathway is responsible for specific intracellular protein degradation. Increased activity of this pathway is common in conditions which elicit increased muscular proteolysis, such as cancer, immobilization, starvation, denervation, lowering of activity, and a variety of exercise conditions. The efficacy of HMB has been demonstrated in both disease and exercise-induced states of catabolism, indicating that it may operate through direct or indirect interference of the Ubiquitine-proteasome pathway.
Although several studies agree that HMB reduces muscle protein degradation, the effects of HMB on muscle protein synthesis have shown mixed results, with studies finding that HMB supplementation results in increases or no change in muscle protein synthesis.
HMB supplementation has been shown to result in increases in phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream signaling targets, indicating an increase in skeletal muscle protein translation. In addition, increased muscle insulin-like growth factor-1 (IGF-1) expression has been observed after the culture of myoblasts with HMB, which may contribute to an increase in protein synthesis.
SIDE EFFECTS
The safety of HMB supplementation has been widely studied. Currently, studies have found no potential adverse side effects when supplementing with HMB in both humans consuming 3 - 6 grams daily, and animals consuming variable dosages. In fact, no adverse effects have been seen in animals consuming enormous amounts of HMB, such as 100 g/d in pigs weighing 20 kg (approximately 100 times the HMB dose used in most human studies).
Studies found that HMB did not negatively affect any indicator of tissue health or function, and no adverse effects on hepatic enzyme function, lipid profile, renal function, or the immune system. Some studies even suggest that HMB may help the immune system and increases wound repair. It was also found that HMB supplementation resulted in a net decrease in total cholesterol (5.8%), a small decrease in systolic blood pressure (4.4 mm Hg), and a decrease in LDL-cholesterol (7.3%) in subjects with hypercholesterolemia.
mass, strength or bone mineral density.
EFFICACY IN THE ELDERLY
Several studies have investigated the efficacy of HMB supplementation in active elderly population. Overall, HMB decreased fat mass and may have increased lean mass over a relatively short term in exercising adults; however, this increase in lean mass did not appear to result in additional increases in muscle strength.
The effects of HMB supplementation in the elderly without an exercise intervention have also been examined. For example, Flakoll et al. investigated the effects of 12 weeks of HMB supplementation in subjects older than 62, living in nursing homes. A significant 0.7-kg increase in lean mass was observed, whereas no changes in lean mass were observed in the placebo group. Moreover, subjects in the HMB group significantly increased leg extensor force, and increased handgrip strength, compared with the placebo group. These improvements in lean body mass and in physical function suggest that HMB supplementation alone, without any exercise intervention, can improve clinical outcomes in the elderly.
mass, strength or bone mineral density.
EFFICACY IN CLINICAL POPULATION
Patients with a chronic disease develop significant muscle loss, which leads to decreased physical function, quality of life, and survival. Numerous nutritional interventions have been investigated in order to counteract muscle wasting; however, many of these interventions have been unsuccessful.
HMB has been investigated for its anticatabolic effects in patients with cancer, AIDS, and chronic obstructive pulmonary disease. Several studies have supported the efficacy of HMB to attenuate muscle loss in cancer cachexia. For instance, May et al. recruited patients with solid tumors with a weight loss of greater than 5%. Patients were assigned to HMB 3 g/d, arginine 14 g/d, and glutamine 14 g/d, or placebo (a mixture of non-essential aminoacids). In the first group, supplementation resulted in an approximately 1 kg increase of lean mass in 4 weeks.
The efficacy of HMB supplementation in patients with AIDS has also been investigated. The results are similar to the ones observed in patients with cancer: an 8-week supplementation increased lean mass by 2,6 kg. Moreover, HMB supplementation increased CD3, CD4, and CD8 cell numbers, indicating that HMB may improve the immune system in patients with AIDS.
Aversa et al. demonstrated that HMB can prevent glucocorticoid-induced myotube atrophy in cultured muscle cells, suggesting that HMB may prevent steroideal myopathy in patients receiving long-term glucocorticoid treatment.
However, not all studies have found beneficial effects of HMB supplementation in clinical populations. For example Marcora et al. supplemented patients with rheumatoid arthritis with a cocktail of HMB (3 g/d), arginine (14 g/d) and glutamine (14 g/d), or placebo (a mixture of non-essential aminoacids) for 12 weeks. The HMB supplementation did not result in any change in lean mass, strength or bone mineral density.
EFFICACY IN ATHLETES
Previous studies have investigated HMB supplementation in athletes. The anti-catabolic effect of HMB is well documented, but studies which aim was to determine its effect upon skeletal muscle strength and fatigue have shown mixed results.
Wilson et al. noticed that consuming HMB prior to exercise was able to prevent LDH values from significantly increasing following muscle damaging exercise. In another study, the same Authors discovered that a short-term supplementation of HMB (3 g/day) was able to reduce the serum creatine kinase (CK) increasing after a high-volume resistance training; CK increased by 104% in HMB group, and by 309% in the placebo group.
Pinheiro et al. studied the effects of HMB on muscle strength and resistance to fatigue in male rats. Both muscle tetanic force and resistance to acute fatigue were increased by HMB supplementation. Moreover, HMB also increased the ATP and glycogen content in both white and red portions of gastrocnemius muscle. These results support the proposition that HMB improves muscle strength generation and performance during intense contractions.
Portal et al. studied the effects of HMB supplementation in elite adolescent volleyball players, in a prospective, randomized, double-blind study. HMB had no significant effect on aerobic fitness or on anabolic, catabolic and inflammatory mediators (GH, testosterone, IGF-1, cortisol, IL-6 and IL-1). On the other hand, HMB supplementation was associated with greater increases in muscle mass, muscle strength and anaerobic properties suggesting some advantage for its use in athletes.
A meta-analysis by Nissen at al. of nine studies found that HMB resulted in significant gains in muscle size, lean mass (0,28%/week) and strength (1,4%/week).
On the other hand, another meta-analysis of eleven studies concluded that 3 to 9 weeks of HMB supplementation resulted in only small to trivial increases in muscle strength and size, regardless of training experience. The discrepancies in these results may be due to many factors, including clustering of data, small samples, poorly designed, and non standardised training protocols.
CONCLUSIONS
There is compelling evidence that HMB supplementation may be useful for clinical muscle wasting conditions including AIDS, cancer, bed-rest, and during periods of caloric deficits. The efficacy of HMB supplementation in athletes and healthy population seems to lack of evidence. HMB is safe at usual dosage (3 g/day), and appears to have promising effects on various markers of health, including blood pressure and LDL-cholesterol.
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