What Is HICA?
by the Labrada Research Team
HICA-Max™ is one of the newest additions to the Labrada Nutrition line, and presents a new pathway to supporting muscle growth for everyone, male and female, pushing muscle to the point of breakdown during vigorous weight lifting session or power workouts. HICA-Max™ is designed to work in a catabolic environment. Recreational lifters easing through a simple circuit or group fitness class are unlikely to find benefit. Heavy lifters will benefit from this novel ingredient.
What is the Active Ingredient in HICA MAX?
The active ingredient in HICA-Max™ is L-α-hydroxyisocaproic acid, abbreviated to HICA. Chemical nomenclature, (the system that defines proper naming of chemicals) recognizes other names for HICA, including 2-Hydroxy-4-methylpentanoic acid, 2-Hydroxy-4-methylvaleric acid, and leucic acid. HICA is a metabolite, or degradation product of leucine, the essential branched chain amino acid. The conversion rate of leucine to HICA is very small, so taking lots of leucine will not provide effective levels of HICA.
To review, proteins, including skeletal muscle contractile protein, are composed of chains of amino acids. In skeletal muscle, there are two proteins that are involved with the actual contraction and relaxation that you know best as “flexing.” These are actin and myosin. In these proteins, branched chain amino acids are present in much higher concentration than other proteins. Branched chain amino acids include: leucine, isoleucine, and valine.
Hormone Like Properties
In addition to being a structural amino acid, leucine also has “hormone-like” properties; isoleucine and valine do not appear to, at least to a measurable degree. Leucine is a significant stimulator of the anabolic pathway that is a vital part of building new muscle called mTOR. When mTOR is activated, it turns on the muscle building machinery in muscle cells. Normally, leucine is not present in the muscle cell in its “free” form. Rather, it is rapidly incorporated into proteins. Certain other amino acids – namely glutamine, alanine, and taurine, are present in concentrations that are much higher. Free leucine is present in significant quantities during two conditions, after eating and during muscle breakdown, (also called proteolysis). Proteolysis is a consequence of the mechanical stresses of exercise, and changes in the acidity of the cell. The “anabolic” effect of leucine appears to peak out at 0.135 g/kg/day. Mega-dosing may add additional benefits, but it appears to require about 20 grams in a single serving.
Knowing that, it should be no surprise that the metabolites of leucine have a physiologic effect as well. Metabolites are new chemicals created as leucine is degraded. Leucine trades off the NH2 (amine group) to replenish the muscle’s pool of glutamine and alanine, becoming α-ketoisocaproic acid (KIC). KIC can be further metabolized to form HMB, a supplement which can be quite beneficial to aging adults by supporting lean mass retention, but has not shown convincing evidence of efficacy in young adult athletes.
A different pathway in the leucine degradation pathway produces the hydroxy-analog of KIC, L-α-hydroxyisocaproic acid (HICA). HICA has not been studied to the extent that KIC has, let alone leucine. Therefore, much of its promise is predicated upon research that is not directly related to muscle growth or body composition support.
It is known that leucine consumed orally, either in a meal or as a supplement, passes through the liver with little loss to the BCAT enzyme that degrades it to KIC. As KIC is the precursor to HICA, therefore leucine supplementation is not a direct method of providing HICA.
The primary leucine pool is in skeletal muscle. This tissue is one that can functionally undergo catabolism, as opposed to other tissue which are generally homeostatic (in a balance, neither growing or breaking down). During starvation, stress, or extreme exercise, the contractile proteins can breakdown and release amino acids. As the BCAAs are in high percentage in contractile protein, this “floods” the muscle cell with free BCAAs, especially leucine. Here is where the majority of KIC and HICA and produced. KIC can be shuttled to the mitochondria of the muscle for energy (ATP) production, but not to a major degree. Instead, it is degraded down to acetoacetate, a ketone body. Think of the ketogenic diets, this is what is released to induce ketosis (from several amino acids, not just leucine). KIC can also be a donor carbon base to regenerate glutamine and alanine which are needed to promote other cell functions.
HICA Is NOT Leucine Nor KIC
KIC has a double bonded oxygen (=O) in place of the amine group (NH2) which is tightly bound to the rest of the molecule. HICA instead has a hydroxyl group (OH) which can be more easily removed. HICA is not just another form of KIC or leucine. Leucine, and to a greater degree KIC, increase the release of insulin during a meal, and increase the cell response to insulin relative to its anabolic signaling. HICA does not appear to have these properties.
Instead, HICA appears to be effective in binding the waste buildup that occurs during proteolysis (protein breakdown) during catabolic events, like exercise and starvation. Most people are familiar with lactic acid. It is produced when the muscle outworks the oxygen supply. Normally pyruvate (pyruvic acid) is shuttled to the mitochondria to be burned for additional calories. However, when oxygen is low relative to the work being done, pyruvate is turned into lactate (lactic acid). This is the fatiguing burn felt during longer sprints or higher rep sets. HICA absorbs some of the acid (H+ or hydrogen ions), reducing the effect of lowering the pH (or making more acid) the inside of the muscle cell. When the pH drops much below normal, the muscle cell stop producing ATP and “burns out” until given time to recover.
Another waste product produced a catabolic event is ammonia (NH4+). Ammonia is a waste product in nearly all creatures. Birds excrete it as uric acid; mammals, including humans, convert it into urea which is a major component of urine. However, ammonia is nitrogen-rich (the N in NH4+), so for those seeking to achieve a positive nitrogen balance (the original measure of anabolic steroids effects on the metabolism), it seeks wasteful to “piss it away.” In fact, it is not necessary to do so as long as the body can use it to build high-value molecules, such as leucine. Reducing the “ammonia strain” is an active area of research, as it is a factor leading to peripheral fatigue. Reducing acid build up in the cell, and ammonia buildup in the blood allows for longer, high intensity work.
Remember, HICA is leucine that has had the NH2 replaced with an OH. Thankfully, that is not an irreversible process. Transaminase and reaminase enzymes can attached an NH2 in place of the OH, creating leucine. Thus, HICA can also serve as a leucine precursor. Nearly thirty years ago, people with failing kidney function were placed on low-nitrogen diets, but often suffered from relative protein deficiency (protein being the main source of nitrogen in the diet). Patents were acquired relating to the use of keto- and hydroxyl-analogs (metabolites) of amino acids to supplement the protein intake of kidney failure patients. This improved lean mass retention and nitrogen balance for this group of people. Normally, this is not an issue for most, but during catabolic breakdown, the loss of leucine can be more quickly replaced. HICA can also be oxidized to create KIC, possibly providing some the of effects of that agent.
There are questions about where HICA performs its actions. It is taken up by the MCT transporter, so it should be bioavailable orally. Type 2 muscle fibers, or slow-twitch fibers, may take in HICA more readily. This is due to their greater aerobic capacity. Type 2 fibers are packed with mitochondria which use oxygen to create energy. Type 1 or fast-twitch fibers are explosive and burn up pre-made ATP, fatigue, and then create more quickly.
What Are the Effects of HICA?
If HICA gets into the muscle cell, it can reduce acid buildup, allowing for longer periods of high-intensity activity before the muscle cell fatigues due to IMP-buildup and decreased acetyl-CoA. Binding ammonia also reduced fatigue and offers a new pool of leucine for muscle repair, and possibly mTOR activation. In the bloodstream, clearing the circulation of waste products (lactate and ammonia) slows the progression of fatigue.
As to how HICA may increase lean mass, it appears to be a function of maintaining the muscle cell in a functioning state by neutralizing the waste products created during high-intensity exercise, and keeping cellular energetic mechanisms functioning during recovery. Also, providing a reserve pool of leucine is always beneficial. HICA is likely short-lived in the body, so it would be best taken 20 minutes prior to a workout.
HICA is a metabolite of leucine, via KIC. However, leucine supplementation does not elevate blood levels of HICA. Therefore, HICA supplementation is necessary to achieve efficacious levels in muscles.
HICA binds H+ (acid) which builds up in the muscle cell as work exceeds the aerobic threshold (e.g. high-intensity lifting, sprinting).
HICA binds ammonia (NH4+) which builds up in the blood and creates fatigue.
HICA can be reaminated, providing a pool of leucine for post-workout recovery and cell-signaling.
New Muscle Growth Stimulation with HICA MAX by Lee Labrada