Ribose and Its Effect on Energy Recovery in Heart and Skeletal Muscle
Terri L. Butler, Ph.D.
Under conditions of physical duress the body’s energy resources become depleted. In particular, intracellular levels of the body’s primary energy carrying molecule, adenosine triphosphate (ATP), are lowered significantly. Since cells and organs need adequate energy in order to maintain integrity and function, it is essential that the supply of ATP be replenished soon after it is consumed. This is possible over the short term in the presence of oxygen via the respiratory metabolic pathways. However, when the oxygen supply is inadequate, even temporarily, energy metabolism is impaired and ATP molecules are not regenerated quickly enough to meet the body’s energy demands.
For example, when the myocardium becomes oxygen depleted due to ischemia (restricted blood flow to the heart) resulting from occluded arteries, heart attack, heart surgery, organ transplantation or other surgery, myocardial levels of ATP will fall dramatically and can take up to 10 days to recover.1,2,3,4,5,6 Under conditions of such energetic depletion myocardial function is compromised and there is an increased risk of permanent loss of myocardial tissue.
Even in lower risk situations, such as healthy individuals who are pushing their physical limits by intense exercise, ATP reserves can become depleted and take several days to recover.7, 8, 9, 10, 11
Slow replenishment of ATP in both myocardial and skeletal muscle tissues has been attributed to the low rate of de novo synthesis and slow recovery of ATP and its precursors via the salvage pathways.2, 3, 10, 12 Since replenishment of ATP is likely to enhance the functional recovery of these tissues investigators have sought methods of improving the salvage rates and increasing de novo synthesis. Interestingly, in a wide range of studies several investigators have found that ATP recovery can be stimulated in both myocardial and skeletal muscle tissues by administering a simple sugar called ribose. 3, 6, 10, 12, 13, 14, 15, 16, 17, 18, 19
Ribose is the substrate for formation of 5-phosphoribosyl-1-pyrophosphate (PRPP). PRPP is, in turn, used in de novo synthesis of nucleotides such as ATP, adenosine, and inosine (Figure 2).3, 12, 14, 24 PRPP is also an essential participant in the salvage pathways for ATP regeneration (Figure 3).3, 12, 14, 24 Nucleotides, including ATP, are essential energy sources for basic metabolic reactions and play important roles in protein, glycogen and nucleic acid synthesis (ribonucleotides and deoxyribonucleotides), cyclic nucleotide metabolism, and energy transfer reactions.
Figure 2. The role of ribose in de novo synthesis of ATP.
Figure 3. The role of 5-phosphoribosyl-1-pyrophosphate (PRPP) in the ATP salvage pathway.
Ribose plays a vital role in both myocardial and skeletal muscle metabolism, largely through its participation (as a precursor to PRPP) in the synthesis of ATP, adenine nucleotides, and nucleic acids. In these tissues the PPP is inefficient due to low availability of glucose-6-phosphate dehydrogenase.13 Supplemental ribose administration allows the rate-limiting glucose-6-phosphate dehydrogenase step in the PPP to be bypassed, thereby directly elevating PRPP levels.14, 15, 18, 24, 25 Elevated PRPP levels are then available for increased adenine nucleotide biosynthesis which accelerates replenishment of depleted cardiac and skeletal muscle adenine nucleotide pools. This is the key to recovery of depleted ATP levels after ischemia or strenuous exercise.
The metabolic basis for the effectiveness of ribose is apparently not species specific because glucose-6-phosphate dehydrogenase is the rate limiting enzyme in the heart and skeletal muscle PPP for rats, dogs, and swine, as well as humans.14 Since this enzymatic reaction is the rate-limiting step in the PPP that limits the available PRPP pool and thus the adenine nucleotide levels, the enzymatic basis for the effectiveness of ribose, i.e., the formation of PRPP by bypassing the G-6-PDH reaction step, is the same for these different species.
Ribose Effects in the Heart
Knowledge concerning the effect of ribose in the heart has been gathered from many laboratory and clinical studies of human and animal myocardial tissue and function. These studies have documented several positive effects of ribose including improved ventricular function and enhanced recovery of myocardial ATP and adenine nucleotide levels following ischemia, increased exercise tolerance in patients with stable coronary artery disease, and improved thallium-201 redistribution in cardiac imaging applications. Myocardial tissue becomes oxygen depleted when blood flow to the heart is restricted. A persistent consequence of this ischemia is a substantial lowering of tissue energy, as evidenced by decreased myocardial ATP levels. These lowered energy levels are in turn correlated with depressed cardiac function.2,3 The correlation between decreased ATP levels and depressed myocardial performance has spurred researchers to develop methods of metabolic intervention into adenine nucleo tide degradation and/or biosynthesis in order to restore myocardial ATP levels.
In a series of oxygen depletion studies in the myocardium using asphyxia recovery and ATP depletion models evidence was gathered that PRPP availability limits adenine nucleotide synthesis by both the de novo and salvage pathways.12,13,24,25 By providing ribose to the myocardium a pronounced stimulatory effect on PRPP synthesis occurs. The presence of ribose allows the rate-limiting step in the pentose phosphate pathway, the G-6-PDH enzymatic reaction, to be bypassed, leading to the production of PRPP. This increase in PRPP levels is noted to be accompanied by accelerated cardiac adenine nucleotide synthesis and improved global heart function. Thus, ribose restores cardiac energy reserves and positively affects myocardial function.
The effect of orally-administered ribose on exercise tolerance in stable coronary artery disease patients has also been studied.26 Two positive baseline treadmill studies were performed for eligibility into this study. The criterion for inclusion was development of moderate angina and/or ST-segment depression (an indicator of ischemia) on the electrocardiogram. Patients were randomized into two groups. Ten patients received placebo (glucose) for three days and another 10 patients received ribose dissolved in water for the same time period. A final treadmill evaluation was performed in all patients after taking the supplement. In the ribose-treated group, the mean walking time to ST-segment depression was significantly greater than in the placebo group (p < 0.002). The time to both ST-segment depression and onset of moderate angina was also prolonged significantly in the ribose group compared to its pre-ribose baseline (p<0.005). These results show that patients who had been given ribose were able to exercise longer without chest pain or evidence of ischemia than patients who did not receive ribose.
Ribose also enhances the detection of hibernating myocardium during diagnostic procedures such as thallium imaging or dobutamine stress echocardiography. In two swine models, ribose infusion after transient ischemia modified thallium-201 (201TI) clearance in both ischemic and non-ischemic myocardial regions, resulting in faster 201TI redistribution.27,28 Furthermore, placebo-controlled clinical trials have also found that intravenous ribose infusion enhances thallium-201 redistribution in humans.29,30 One such trial addressed whether or not an intravenous infusion of ribose could facilitate 201TI redistribution after transient myocardial ischemia in patients with coronary artery disease and thus improve the ability to detect jeopardized but viable myocardium.29 Seventeen patients with documented coronary artery disease and chronic, stable angina were enrolled. Each patient underwent two separate exercise tests, one with saline infusion and one with ribose, performed 1 – 2 weeks apart. In each test an injection of 201TI was given and two subsequent imaging procedures were performed. Post-exercise and initial imaging, patients received the infusion of either ribose or saline. Imaging was performed again at 1 hour, followed by a rest period of 4 hours. Following the rest period imaging was performed one final time. The results revealed that at both 1 and 4 hours post-exercise there were significantly more reversible defects identified when patients were given ribose versus saline. In another 201TI study with a similar protocol, but with imaging at 4 and 24 hours, results showed that there were more defects detected at 4 hours post-exercise when ribose infusion was given than at 4 and 24 hours with saline infusion.30 The conclusions from both of these studies imply that ribose substantially improves the identification of viable ischemic myocardium using 201TI imaging after exercise, suggesting improved post-ischemic myocardial function with ribose administration.
Another research study reported that ribose infusion in conjunction with dobutamine stress echocardiography increases the contractile response in hibernating regions of the heart.31 In a placebo-controlled double-blind study twenty-five patients with ischemic cardiomyopathy were infused with either D-ribose or dextrose placebo for the 4 hours prior to dobutamine stress echocardiography. On day two the patients were crossed over to the alternate treatment. During dobutamine stress echocardiography more dysfunctional wall segments responded with improved wall motion when D-ribose was infused prior to the procedure as compared to placebo (p = 0.02). In patients who then underwent coronary artery bypass surgery the predictive sensitivity for functional recovery of the segments identified during the D-Ribose infusion was greater than those identified during placebo infusion.
A recent review provides the background and rationale for the use of ribose in metabolic support of the heart.32 Evidence such as that discussed above is presented in support of the main hypothesis that ribose is the rate-limiting component in the pathways necessary for the heart to restore depleted adenine nucleotide levels.
Ribose Effects in Skeletal Muscle
Several studies have noted that while healthy skeletal muscle has a large capacity for high-energy phosphate turnover, intense exercise causes significant decreases in ATP and total adenine nucleotides (TAN) pools. One study showed that one week of high-intensity exercise significantly decreased levels of both ATP and TANs in skeletal muscle with no meaningful recovery even after 72 hours of rest.9 This decrease in ATP (23%) and TAN (24%) is reflective of the loss of nucleotides from muscle during and following high intensity exercise. Furthermore, the delayed recovery of ATP and TANs is likely explained by the lack of the availability of 5-phosphoribosyl-1-pyrophosphate (PRPP), the rate-limiting factor in adenine nucleotide synthesis and salvage. A second study found that resting ATP and TAN levels were lowered by 19% and 18% respectively after high intensity exercise training.7 These lowered levels were primarily attributed to an inability of skeletal muscle to completely restore the purines that were lost as a result of high ATP turnover during training periods. Total purines continue to decline in the first few minutes following exhaustive cycle exercise as found in a study of 8 healthy male subjects.11 An average decrease of 6.3% in total purines was seen between the time the exercise period ended and 3 minutes into recovery. This provides evidence that there are rapid changes in TAN levels due to degradation and purine efflux.
In two benchmark studies ribose administered to isolated hind limb muscle fibers in vitro led to increased adenine nucleotide de novo synthesis rates of 3.4 to 4.3-fold and adenine and hypoxanthine salvage rates of 3 to 6-fold.10,33 Fast-twitch red gastrocnemius, fast-twitch white gastrocnemius, fast- twitch mixed plantaris, and slow-twitch red soleus muscle fiber types were studied. The greatest increase in both de novo synthesis and adenine and hypoxanthine salvage rates were seen in the low-oxidative fast-twitch white gastrocnemius muscle, with significant increases in the other muscle types as well. The importance of ribose in skeletal muscle energy metabolism was noted, and its impact on PRPP availability thought to be most critical.10
In a follow-up study these researchers found that without added ribose adenine salvage rates were low in both resting muscle and post-contracted recovering muscle, but with the addition of 5mm ribose to the perfusion medium these rates increased 5-fold.34
They also found that increasing the adenine nucleotide salvage rates by adding ribose to the perfusion medium did not result in a larger ATP pool. Instead, they found that, in spite of increased salvage rates, ATP concentrations were controlled within narrow limits by activation of adenine nucleotide degradation.35
In a study of 16 human athletes those subjects taking supplemental ribose had a larger increase in mean power over 5 days of training (4.2% vs. 0.6%), and greater peak power output at the last sprint session (11.4 watts/kg vs. 10.4 watts/kg, p=0.05 time) than the placebo group. 36 In this study 8 subjects consumed ribose and 8 subjects consumed glucose placebo, each at a dose of 10 grams two times per day. The study consisted of three phases, a loading phase, a training phase, and a recovery phase. During the loading phase, which was 72 hours long, the subjects did not exercise but consumed their respective supplement twice a day. The subjects then entered the training phase, which was 5 days long, during which they continued taking their supplements and began high intensity exercise bouts twice per day. The exercise bouts consisted of 15 x 10 second cycle sprints at a workload of 0.07 kg/kg body weight with a 50 second rest between each sprint. After the training phase the subjects entered a 65 hour recovery phase where they continued taking supplemental ribose or glucose placebo, but did not exercise.
Throughout the training sessions the mean power output was consistently higher in the subjects who consumed ribose than in the subjects who consumed glucose placebo. (Figure 4). Also, the percent fatigue was consistently less in the ribose group than in the placebo group (Figure 5).
Figure 4. The mean power output per kilogram body weight for athletes consuming ribose supplement or glucose placebo. For each group n = 8.
Figure 5. Percent fatigue in athletes consuming ribose supplement or glucose placebo. For each group n = 8.
Another aspect of the same study showed that ribose supplementation partially attenuated the decrease in TAN levels after the 5 days of exercise (p < 0.05).37 While the placebo and ribose groups displayed a similar pattern of recovery of TAN levels, the ribose group recovered to pre-exercise levels after the 65 hour recovery period, but the placebo group remained at 23% below pre-exercise levels (Figure 6).
Figure 6. Total adenine nucleotide levels from muscle biopsies in athletes consuming ribose supplement or glucose placebo. For each group n = 8.
The fact that ATP and TAN levels decrease during exercise and normally do not recover even after three days of rest indicates that without supplementation skeletal muscle has a limited ability to maintain peak performance during periods of repeated high-intensity exercise. However, the studies reviewed here indicate that the administration of ribose leads to an increase in the power output in athletes and improves the ability of skeletal muscles to quickly recover their energy levels after high intensity exercise.
Indeed a study of exercise performance over 4 weeks in male bodybuilders showed a significant increase in the number of total repetitions performed in bench press exercises in athletes taking ribose compared to athletes taking glucose placebo.38 The subjects were randomly divided into two groups, 5 subjects consuming ribose and 7 subjects consuming glucose placebo. The supplements were taken in divided doses, 5 grams 15 minutes prior to exercise and another 5 grams immediately post-exercise. The ribose group experienced a significant increase in the number of bench press repetitions performed to muscular failure (Figure 7, +29.8% ribose vs. +7.42% placebo, p = 0.046).
Figure 7. Increase in number of repetitions to failure in bench press exercise in male bodybuilders after 4 weeks of supplementation and exercise training (placebo n = 7, ribose n = 5).
Ribose and its Role in the Pentose Phosphate Pathway
Ribose is a naturally occurring pentose monosaccharide. It is used by the body to synthesize nucleotides, nucleic acids, glycogen, and other important metabolic products. Ribose is formed in the body from conversion of glucose via the pentose phosphate pathway (PPP, also known as the hexosemonophosphate shunt or the phosphogluconate pathway, Figure 8).
Figure 8. The pentose phosphate pathway (PPP) and the point of entry for ribose into the pathway. 5-phosphoribosyl-1-pyrophosphate is represented as PRPP.
Supplemental ribose enters the PPP by being phosphorylated to R-5-P by ribokinase. The R-5-P thus formed can be utilized to a) generate glucose by reverse flux up the PPP 20, 21; b) form pyruvate through glycolysis 21, 22; or c) synthesize nucleotides 23 which are needed for ATP production. In this way ribose is utilized in animals and man in many different tissues, including the heart and skeletal muscle.
ATP, the body’s primary energy-carrying molecule, is necessary for maintenance of cellular integrity and function. Ribose plays a key role in the generation and recovery of ATP. Adding ribose to the ATP-depleted myocardial or skeletal muscle environment stimulates recovery of ATP levels. This enhancement of ATP recovery may play an important role in improving the overall health, lifestyle, and level of fitness in people with cardiovascular disease as well as in athletes who are pushing their exercise limits and depleting their energy reserves.
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