Creatine Monohydrate

HMB is a metabolite of the branched-chain amino acid leucine and is found naturally in small quantities in catfish, various citrus fruits, and breast milk. Leucine, an essential amino acid, is used for protein synthesis, with the residue being transaminated to alpha-ketoisocaproate (KIC) and then partially oxidized to form HMB. The HMB derived from leucine is converted to beta-hydroxy-beta­methylglutaryl CoA (HMG-CoA) in some tissues and serves as a key carbon source for cholesterol synthesis in various cell types.

This de novo cholesterol synthesis is believed to be behind HMB’s performance-enhancing effects. During periods of cell growth and/or differentiation, HMG-CoA may be a rate-limiting step for cholesterol synthesis, which appears to be a restrictive factor for both cell function and growth. HMB feedings are believed to saturate cells with a source of HMG-CoA, thus providing the tools for cells to undergo a maximal growth response (for strength/power athletes that would be a hypertrophic and/or hyperplastic response with regard to skeletal muscle fibers).

In Vitro Studies

Studies conducted on HMB’s actions at the cellular level have been done in both animal and human cell types. The effect of HMB on skeletal muscle metabolism was investigated by Kostiuk et al. using isolated muscle strips from rats and chicks. Tissues were exposed to different concentrations of HMB and the rates of protein degradation and protein synthesis were measured. This investigation demonstrated HMB inhibited proteolysis by an average of 80% while at the same time increased protein synthesis in both muscle tissues. Cheng et al. also investigated the muscle protein effects of HMB in two cell lines, H9C2 (heart cells) and C2C12 (skeletal muscle cells). Samples were differentiated in culture to myotubes and exposed 2 to 4 days to a to 6 mM HMB. Scientists observed increased beta oxidation of palmitate by 30% decreased lactate dehydrogenase from myotubes by 25% and an increased cellular expression of creatine kinase (CK) by 25%. These results suggest HMB may alter muscle cell metabolism by increasing cellular oxidative capacity and enhancing the expression of muscle-specific proteins-proven by the increased cellular expression of CK.

HMB may also play a part in the immune response to exercise. This effect could apply to preventing overtraining syndrome in strength-power and endurance athletes in whom the immune system is compromised as well as in various medical conditions. In vitro studies investigating the effects of HMB in this regard have demonstrated a positive effect on lymphocytes. Nonnecke and colleagues demonstrated that HMB in high concentrations affected DNA synthesis of bovine lymphocytes in a cell culture medium with adequate in vitro study, HMB was added to chicken-macrophage cultures in various concentrations (range, 100 to 1000 mM). Macrophages are important to immunity because they are involved in producing antibodies and in the mediation of cellular immune responses. In addition, they also participate in the presentation of antigens to lymphocytes. With the addition of HMB, the number of macrophages increased by 20% and nitrite production increased by 29%. In chicks receiving HMB the number of Sephadex-elicited macro phages from peritoneal fluid increased two-to threefold. These data demonstrate HMB exposure induces the generation of macrophages in culture and increases nitrite production and the phagocytic capabilities of macrophages.

Animal Studies

Animal data regarding the beneficial effects of HMB on performance and growth parameters are equivocal and much less intriguing than the human data. Although in vitro data from Kostiuk et al. demonstrated an antiproteolytic and anabolic effect in skeletal muscle, work from Papet et al. showed that high-dose HMB supplementation in lambs had no effect on whole-body protein turnover or skeletal muscle protein synthesis.

Human Studies

Recent human studies suggest HMB displays anticatabolic and anabolic activity in skeletal muscle. Nissen et al. conducted a two-part study to determine whether the administration of HMB to subjects undergoing a weight-training program would elicit any positive effects when compared against those training without supplementation. In part one, untrained subjects randomly received three differing dosages of HMB , and two different protein diets (117 or 175 g/day). The training protocol worked each muscle group once or twice weekly with either free weights or machines. Sessions alternated emphasis between upper and lower body exercises with at least 1 day of rest between workouts. The protocol lasted 3 weeks, with each subject getting 10 total workouts . Each exercise included two warm-up sets with 10 repetitions at 30-60% of the subjects 1-RM. Work sets were performed with three sets of 3 to 5 repetitions at 90% of the 1-RM. The exercises consisted of the following: free­weight bench press, machine latissimus dorsi pull-downs, machine seated row, machine pectoral fly, free-weight preacher biceps curl, and machine triceps push-down; leg press machine, standing calf raise machine, leg flexion machine, leg extension machine, 45­degree inclined situp, inclined leg lift, and back extension. An advanced lifting protocol was used in part two of the study. Twenty eight subjects were supplemented with either 0 or 3.0 g of HMB per day and trained 2 to 3 hours per day 6 days a week for 7 weeks.

In part one of the study, HMB supplementation significantly lowered training-induced muscle proteolysis as measured by urinary 3-methylhistidine excretion during the first 2 weeks of the study. A reduction in plasma creatine kinase was also observed with HMB administration. In subjects receiving HMB, strength increases were greater than those observed in control subjects. When looking at this study critically, a few important issues must be addressed. This was a short-term study and untrained subjects were used. Therefore, although gains in strength were observed, it is impossible to attribute those improvements to the HMB supplement only. Initial improvements in strength in untrained individuals could be a result of increased voluntary activation of muscle (neural adaptation), rather than the accretion of protein. Staron et al showed that approximately resistance training sessions are required to induce increases in lean body mass or muscle mass. Thus, using untrained subjects during a short-term trial severely limits drawing any conclusions to the benefit of HMB in terms of increasing muscle mass and strength.

In the second study, fat-free mass increased in the HMB­supplemented group at various intervals throughout the study, but not at the conclusion of the study. After the seventh week, strength improved in the bench press, but not the squat or hang clean exercises in the HMB-supplemented group. Thus, over time it is apparent that the effects of HMB may actually diminish. In this phase of the investigation, trained subjects were used, but the control group was stronger at the onset of the study. Therefore, these subjects did not attain the same percentage gains as the two groups receiving HMB.

Although the majority of research is conducted in male subjects, using female subjects is important as well. This research proves valuable from a scientific standpoint because of the differing hormonal milieu in women as well as from a health standpoint (i.e. weight control, prevention of osteoporosis, as well as possible safety concerns for pregnant females). With the increasing involvement of women in strength training and their interest in altering body composition, science should address the female organism’s response to nutritional ergogenic aids. To determine if the same antiproteolytic effects occur in women as in their male counterparts undergoing vigorous strength training, scientists from Iowa State University, in Ames, Iowa investigated the effects of HMB (3 g/day) on 36 nonexercising females, and a second study investigated HMB supplementation (3 g/day) or a placebo given to 37 women undergoing a 3 day-per-week resistance training program. Body composition was measured via total body electrical conductivity (TOBEC) in the first part of the study and underwater weighing in the second. In contrast to the study conducted by Nissen et al, these researchers determined that HMB supplementation, combined with weight training, increased gains in lean body mass and strength. Untrained sedentary subjects receiving HMB showed no changes in lean or fat mass.

Vukovich et al. studied the effect of calcium HMB on maximal oxygen consumption and maximal blood lactate concentration in endurance-trained cyclists. During this trial, eight cyclists randomly completed three separate supplementation periods. Each supplement was administered for 2 weeks followed by a 2-week washout period. Supplements administered to the subjects were HMB (3 g/day), leucine (3 g/day), and a placebo (3 g/day). Before and after each supplementation period, subjects completed a VO2peak test with blood samples obtained immediately following exercise to determine the maximal appearance of blood lactic acid. After 2 weeks of HMB supplementation, a significant increase in VO2peak was noted for the calcium HMB group. VO2peak was unaffected by leucine and placebo supplementation. The HMB group also showed a significantly greater time to reach VO2peak, whereas leucine and placebo elicited no effect on this variable. Maximal blood lactic acid concentrations were unaffected by supplementation but tended to be higher following HMB supplementation. Thus, the authors concluded that HMB supplementation could have positive effects on performance by increasing V02peak Although these results may not appear to be of importance to the strength athlete per se, it may be beneficial to those athletes participating in running events between 400 and 1600 meters.

Whereas HMB alone appears to have limited effects in an otherwise healthy population, some researchers have examined the effects of ingesting a calcium HMB/glucose supplement combined with or without creatine during sprint and strength-training exercises. In a double-blind and randomized manner, 41 NCAA Division IA football players were match-paired and assigned to supplement their diets for 28 days with either -

1) A placebo containing 99 g/day of glucose, 3 g/day of taurine, 1.1 g/day of disodium phosphate, and 1.2 g/day of potassium phosphate

2) The PotPh mixture with 3 g/day of calcium HMB

3) the PotPh/HMB mixture with 15.75 g/day of HPCD pure creatine monohydrate.

In this study, subjects participated in a resistance-training program and an agility/sprint training program . On days 0 and 28, subjects performed 126-second sprints on a computerized cycle ergometer with 30-second rest periods between sprints. Subjects also performed maximal repetition tests at 70% of estimated 1-RM on the isotonic bench press, upright squat, and power clean. Using ANCOVA and ANOVA statistical techniques, this group showed that work output tended to be greater in the HMB and HMB/creatine trials. Mean change in work tended to also be greater in the HMB and HMB/creatine groups. Gains in lifting volume tended to be greater in the HMB/creatine group for the bench press squat , and clean. Results revealed that adding creatine to HMB could enhance strength and/or anaerobic capacity. However, additional research is necessary because this investigation did not control for creatine effects by using a creatine-only group.

Because of the possible effects of HMB in decreasing proteolysis and increasing protein synthesis in skeletal muscle, this compound may be effective in the medical treatment of certain conditions such as certain muscle wasting diseases or in postsurgical recovery. Both practitioners and patients find it particularly interesting that HMB may have beneficial effects in preventing the profound decrease in muscle tissue and immune system function observed in the late stages of AIDS. In certain conditions L-arginine and L-glutamine have been shown to increase immune function in humans and to have beneficial effects on skeletal muscle. In an interesting study presented at the XII World AIDS Conference in June of 1998, Clark et al. investigated the possibility that an amino acid combination administered with HMB could result in a synergistic action positively affecting muscle metabolism and immune function. Subjects were recruited from HIV clinics to participate in a randomized, double-blind, placebo-controlled 8-week study in which they received an amino acid mixture containing 14 g arginine, 14 g glutamine, and 3 g HMB daily. Lean body mass and fat mass were measured by an air displacement plethysmography at 0, 4, and 8 weeks. The abstract presented data from 16 subjects and results showed subjects who consumed the amino acid/HMB mixture gained 3.00 ± 0.50 kg , whereas the placebo group gained 0.37 ± 0.84 kg.Weight gain with the experimental group was predominately lean tissue and fat 0.60 ± 1.70 kg). The placebo group did not gain any lean tissue, but did accrue fat . Measures of immune system integrity demonstrated that the amino acid/HMB mixture increased absolute CD4 numbers by 17.3 ± 28.2 cells/mm versus 49.0 ± 27.4 and absolute lymphocytes by 0.29 ± 0.14 1000/mm versus -0.31 ± 0.15. Although it appears that HMB might provide a useful tool to those treating HIV-associated wasting syndrome, it would have been informative to have one group of subjects ingesting L-arginine and L-glutamine alone and in combination with creatine. As was previously demonstrated at the XI International Conference on AIDS, Daniel et al. showed that a formula containing creatine was effective in increasing total body mass in HIV-positive patients and, therefore, this presents an interesting avenue of future investigation for individuals afflicted with this disease.

Safety and Toxicity

According to existing human data, HMB appears to be safe and well tolerated. Studies ranging in length from 1 to 8 weeks have shown that up to 3 g/day of HMB is safe in male and female subjects, this is supported by the lack of adverse physical effects determined by blood chemistry analysis.

PCr’s major cellular function is to maintain metabolic flux during the early onset of exercise and high-intensity work performance. Given the observed greater ATP production associated with PCr, and coupled with the increase in PCr associated with creatine supplementation, the potential for an increase in anaerobic work output is fully justifiable. Moreover, the maintenance of PCr concentrations appears to correlate well with the development of fatigue in that its decrease is associated with a decline in muscular force. Infante et al. showed a direct relationship between external work and PCr breakdown in the frog rectus abdominis muscle. Spande and Schottelius also showed a direct relationship between force production and PCr stores in isolated mouse soleus muscle that was tetanically stimulated. In this model, they observed a decline in PCr that was directly proportional to the development and maintenance of isometric tetanic force.

In humans, Hirvonen et al. concluded that the slowing of running speed during maximal work efforts is related to a decline in the energy production brought forth from ATP and PCr. This effect may be a result of muscle fiber type differences in the endogenous stores of each substrate. This premise is supported by the observations of others who have noted that type II muscle fibers possess higher initial levels of PCr and, consequently, greater rates of PCr usage than do type I muscle fibers during high-intensity exercise. PCr and glycogen recovery also appears to be slower in type II fibers following high-intensity exercise. Moreover, PCr resynthesis during recovery has been shown to be an oxygen-dependent process that exhibits a two-component or biphasic pattern. The first (fast component) has a half-time of approximately 22 seconds, whereas the second (slow component) is longer than 170 seconds. During continuous or intermittent high-intensity exercise, the resynthesis rate of PCr plays an important role in the force capabilities that active muscle can generate owing to the heavy reliance on PCr and ATP.

When PCr levels are not given adequate recovery time, performance is impaired and power output is decreased Conversely, when recovery is prolonged, increased PCr concentration is correlated with greater power output during consecutivecycle ergometer sprints when rest periods of either 90 or 180 seconds are allowed. Thus, the possibility of creatine supplementation increasing PCr recovery is important because it is the recovery of PCr following high-intensity exercise that allows athletes to continue high-intensity activity more effectively. If it is possible to increase the rate of resynthesis and PCr storage capacity through supplementation, then the use of creatine has a valid physiological base from which to assess utility

Coenzyme Q10 (CoQ10), sometimes referred to as ubiquinone, is a lipid-soluble coenzyme produced by respiring organisms and some photosynthetic bacteria. CoQ10 aids in the transport of electrons between enzyme complexes of the inner mitochondrial membrane. Through the process of oxidation phosphorylation, CoQ10 also aids in the production of ATP.

Human Studies

The effects of CoQ10 supplementation have been studied using patients with chronic obstructive pulmonary disease (COPD). Eight patients ingested 90 mg/day of CoQ10 for 8 weeks and showed a significant increase in serum CoQ10 levels with a decrease in hypoxemia at rest. Tread­mill time tended to increase (12.0-14.0 min) with a significant decrease in heart rate during exercise, whereas lactate production decreased. However, pulmonary function and oxygen consumption during exercise were unaltered.

Studies have also been conducted on elite athletes. Twentyfive Finnish top-level cross-country skiers ingested 90 mg/day of CoQ10 in a double-blind, crossover fashion. Supplementation significantly improved the subjects . Also, 94% of the athletes felt their performance and recovery times were improved during the supplementation period versus only 33% during the placebo period.

Conversely, ten male bicycle racers performed graded cycle ergometry before and after supplementation with 100 mg/day of CoQ10 or a placebo for 8 weeks. There was a significant difference in serum CoQ10 levels between groups. Both groups showed improvements in exercise performance, but there were no significant differences between groups.

Snider et al. supplemented 11 highly trained male triathletes with three daily doses of a combination of 100 mg of CoQ10, 500 mg of cytochrome C, 100 mg of inosine, and 200 IU of vitamin E or a placebo for two, 4-week periods. There was a 4-week washout between treatment periods in this double-blind crossover design study. After each treatment period, the subjects ran on a treadmill at 70% for 90 minutes followed by a period of cycling at 70% until exhaustion. There were no significant differences between groups for time to exhaustion, blood glucose levels, lactate levels, and free fatty acid concentrations.

Eighteen male road cyclists and triathletes were supplemented with 1 mg/kg/day of CoQ10 or a placebo for 28 days The subjects were evaluated during and after graded cycling exercise tests. Plasma CoQ10 levels were significantly increased from baseline. Nonetheless, CoQ10 had no consistently significant effect on oxygen uptake, anaerobic and respiratory compensation thresholds, blood lactate, glucose and triglyceride kinetics, heart rate, or blood pressure during and following the exercise protocol.

In 1996, MaIm et al. conducted research on CoQ10 using healthy males. The results showed that CoQ10 might actually cause cell damage under intense exercise conditions. MaIm et al also conducted a follow-up study on CoQ10. Subjects ingested CoQ10 for 22 days while performing aerobic exercise, except on days through the subjects performed high-intensity anaerobic training. The results showed that during an anaerobic cycling test, the placebo group performed significantly better than the CoQ10 group on day of supplementation (9.7 versus 9.3 W/kg for the placebo and CoQ10 groups, respectively). Furthermore, the CoQ10 group had a significantly lower increase in total work performed. Overall, there were no significant differences between the groups , rate of perceived exertion (RPE), respiratory quotient, blood lactate concentration, or heart rate.

CoQ10 may aid in the transportation of electrons with­in the mitochondria and also aid in the production of ATP However, it probably does not enhance endurance performance.

Safety and Toxicity

Studies have been conducted on the safety and effectiveness of CoQ10 supplementation in patients who suffer from heart failure. These studies showed an improvement in the patient’s health status However, the results from a study using healthy males showed that supplementation with CoQ10 may cause some cell damage in the intramembrane compartment of the mitochondria.

L-carnitine is a creatine which contains a short-chain carboxylic acid and has a potential effect on endurance performance because it is a physiological carrier of activated long-chain fatty acids across the inner mitochondrial membrane. Once inside the mitochondria, the long-chain fatty acids are beta-oxidized and carnitine exports acylcoenzyme A compounds. The oxidation of fatty acids in the mitochondria is the main fuel source for skeletal muscle. Also, the carnitine shuttle of a muscle controls the efficiency of the use of fatty acids and the activation of branched-chain amino acid oxidation in the muscle.

The ingestion of carnitine has been speculated to enhance fatty acid oxidation and thus spare skeletal muscle glycogen, and this glycogen-sparing effect may aid endurance performance.

Human Studies

Marconi et al. were the first to investigate the use of carnitine supplementation on endurance performance. Six long distance competitive walkers ingested 4 g/day of L-carnitine for 2 weeks. After the 2-week training period, the subjects’ increased 6% . On the other hand, when the subjects walked 120 minutes at 65%, heart rate, pulmonary ventilation, oxygen consumption, and respiratory quotient remained unchanged. The authors concluded that the slight, but significant increase was probably due to an activation of substrate flow through the TCA cycle.

In a study by Greig et al. two groups of untrained individuals were used in a double-blind, crossover designed study. In the first trial, 2 g of L-carnitine were ingested per day for 2 weeks, and in the second trial, the same dose was given for 4 weeks. Maximal and sub maximal exercise capacity was assessed with a cycle ergometer at 70 rpm. The results showed no significant increase or maximum heart rate.

Gorostiaga et al. conducted a study on ten endurance­trained athletes . The subjects first performed a control test consisting of 45 minutes of cycling at 66% of followed by 60 minutes of seated rest. After 28 days of supplementation with 2 g/day of L-carnitine or a placebo (double-blind, crossover design), the subjects performed the same routine. The results showed a lower respiratory quotient in the treatment group, and there were also trends for an improvement in oxygen uptake and heart rate, but no significant improvements in performance were seen.

In a double-blind, crossover design field study, seven male subjects were given 2 g of L-carnitine 2 hours before the start of a marathon and 20 km into the run. The subjects’ respiratory exchange ratio (RER) was determined before and after the race, and a submaximal performance test was conducted on a treadmill the morning after the race. Supplementation with L-carnitine showed no significant change in marathon running time or RER. Moreover, there were no changes in the sub maximal treadmill test conducted the morning after the run.

One could reasonably conclude at this point that carnitine does not have any consistent effect on endurance performance.