The chemical hydroxymethyl butyrate (HMB) is produced when the body breaks down the amino acid leucine. HMB is promoted as a nutritional supplement that can help speed wound healing and support individuals with muscle-wasting diseases such as cancer and HIV. HMB proponents also tout HMB supplements as a way to slow the muscle wasting that comes with aging.
Research supports some beneficial gains of HMB. It’s been shown to promote muscle gain in individuals who are working out. However, this muscle-promoting effect is dependent on adequate availability of essential amino acids (EAAs). HMB supplements without the support of EAAs have a minimal muscle-building effect.
How Does HMB Work?
HMB and the essential amino acid leucine are closely linked, and it is necessary to understand the relationship between HMB and leucine to understand how HMB works. In addition to being the most abundant essential amino acid in muscle protein, leucine can act as a nutraceutical that helps turn on your body’s muscle-building switch. Some experts propose that the way leucine turns on the process of protein synthesis is via HMB.
HMB is derived from the breakdown of leucine. About 15% of leucine in the blood is irreversibly broken down to ammonia and carbon dioxide. This process involves a series of step-by-step reactions. Taken together, the sequence of reactions that reduce the intact molecule of leucine to its basic components is called a metabolic pathway.
There is more than one metabolic pathway involved in the breakdown of leucine. In a minor pathway, HMB is produced as a byproduct and is proposed to be the active component of leucine. However, only about 5% of leucine breakdown occurs via the pathway that results in HMB. Coupled with the fact that only 15% of leucine is broken down at any given time, the amount of HMB produced by leucine breakdown is a very small percentage of available leucine. As a result, the concentration of HMB in body fluids is far less than that of leucine. Since it is necessary to increase the concentration of HMB many folds above the normal physiological level using dietary supplementation to see effects, it is unlikely that leucine’s effects on muscle protein synthesis are, in fact, mediated by HMB.
When the availability of HMB is increased using dietary supplements, HMB seems to work as a nutraceutical in the same way leucine does. HMB activates the molecular mechanisms involved in the initiation of protein synthesis. Specifically, a non-physiological increase in HMB concentration activates the molecule mTOR.
The molecule mTOR is a key pivot point controlling the initiation of protein synthesis. When mTOR is activated, it launches a series of additional chemicals involved in the initiation of protein synthesis. When all of these molecules are switched on, the process of protein synthesis begins. Consequently, activation of mTOR by excess HMB stimulates the process of protein synthesis.
A sustained increase in muscle protein synthesis should ultimately be reflected by an increase in muscle mass, strength, and function over time. However, HMB alone does not sustain an increase in protein synthesis—any increase in protein synthesis resulting from HMB supplements will last only as long as an adequate supply of essential amino acids does. Once there is a dip in essential amino acids, the HMB effect halts.
HMB Needs Essential Amino Acids (EAAs) to Work
If you activate mTOR but your body doesn’t have enough supportive EAAs circulating in the bloodstream, then you can only increase muscle protein synthesis to a limited extent.
There are nine unique EAAs, and they are vital components of newly-produced proteins. As the classification essential implies, EAAs cannot be produced in the body, and, therefore, the only source of new EAAs is dietary consumption. If you aren’t getting enough EAAs through the protein-rich foods you eat or with EAA supplements, then your only source of EAAs is contained in body protein.
The breakdown of body protein releases the component amino acids, including EAAs, into the cells of the body. Under normal conditions, about 15% of amino acids released by protein breakdown are irreversibly lost to oxidation, and the remainder is reincorporated into protein.
Let’s circle back to HMB: to be effective on its own, HMB must increase the efficiency of the reutilization of EAAs for protein synthesis. However, that process is already 85% efficient, so there is a definite limit as to how much more efficient the recycling of EAAs back into protein can be. Consequently, dietary supplementation with HMB can only work in concert with an excess availability of EAAs.
An excess of EAAs can only occur by two mechanisms: either EAAs must be consumed at the same time as HMB, or the rate of protein breakdown must be accelerated. An increase in protein breakdown would undermine any beneficial effect of an increase in protein synthesis since protein gain is the result of the balance between protein synthesis and breakdown. Thus, HMB can only cause a sustained increase in the net gain of muscle protein if consumed at the same time as an abundant supply of EAAs.
HMB Supplementation Benefits
There are a few conditions that may benefit from HMB supplementation, such as catabolic states involving rapid muscle loss.
Protein breaks down much more rapidly in catabolic states such as critical illness or HIV. This protein breakdown provides extra EAAs that would, under normal health conditions, be oxidized. In these circumstances of increased EAA availability during catabolic states, supplementing with HMB may help to maintain muscle mass and function. However, recommendations for catabolic states generally specify that HMB should be part of a multifaceted approach for muscle maintenance, including resistance training and a high-protein diet for EAA sustenance.
Exercise also accelerates muscle protein breakdown and EAA oxidation. Consequently, HMB may improve the reutilization of EAAs released by protein breakdown for the synthesis of new protein, with the result being improved performance.
Does HMB provide a benefit beyond that of leucine contained in a mixture of EAAs?
The responses to dietary supplementation with only HMB are similar to those resulting from dietary supplementation with leucine alone. Just as HMB requires the presence of elevated levels of all the EAAs, leucine supplementation also requires the co-ingestion of the other EAAs to be effective. When leucine is included in a mixture of all the other EAAs, the physiological response is more robust than the response to leucine (or HMB) alone. This is demonstrated most clearly by the results of two experiments performed in the same laboratory and using the exact same protocol. In one experiment, the effectiveness of HMB was assessed, and in the other experiment, the effectiveness of a mixture of EAAs (containing about 40% leucine) was determined.
The study protocol involved investigating how effective these supplements were at diminishing the loss in muscle mass and function that normally occurs with inactivity. Lean body mass and performance on various physical function tests were determined before and after 10 days of strict bed rest in subjects over the age of 65. Both the HMB and EAA experiments were tested against a placebo.
If the data from all subjects were included in the statistical analysis, the major differences between HMB and EAAs were in terms of the functional tests. The functional tests used in the study have been validated as representative of physical requirements for activities of daily living in older individuals.
The placebo group had major impairments in all physical function tests after 10 days of bed rest. EAA supplementation, but not HMB supplementation, significantly improved outcomes. The time required to go from a standing position to the floor and rise to the feet again (floor transfer) increased by approximately 40% in the placebo group. Floor transfer rate was not significantly affected by HMB supplementation. The group given EAA supplementation, on the other hand, shortened floor transfer time by 6%.
The time required to walk up a flight of stairs increased by 18% in the placebo group, and again HMB had no beneficial effect on this response. EAA supplementation virtually prevented the increase in stair ascent time.
Finally, the number of toe-raises that could be completed in one minute was reduced by almost 80% in the control group and the HMB supplementation group, whereas the loss of this function with bed rest was completely prevented by EAA supplementation.
The bed rest studies cited above are the only direct comparison of the muscle-building effects of dietary supplementation with HMB and a formulation of EAAs. The results clearly demonstrate the beneficial effects of EAAs on preventing declines in physical function, while failing to demonstrate any beneficial effect of HMB alone. These results are consistent with the fact that the stimulation of the synthesis of new proteins requires excess availability of all component amino acids, especially the EAAs. HMB’s activation of mTOR and other molecules involved in the initiation of protein synthesis may result in a transient increase in muscle protein synthesis, but this increase cannot be sustained at a sufficient rate to result in improvements in physical function.
The HMB Takeaway
HMB is widely promoted as a muscle-building molecule that stimulates protein synthesis. While in some circumstances HMB supplementation may provide benefits, direct comparison with EAA supplementation highlights the little benefit of HMB.
Whatever molecular signaling occurs as a result of HMB supplementation can be achieved by taking an EAA supplement that contains leucine. The excess availability of all the EAAs (which is not present in HMB supplements) is required for a sustained increase in protein synthesis. Furthermore, it would not be expected that combining HMB with EAAs would be particularly helpful, as the action of HMB would already be elicited by the EAAs.