Lactate in CFS
Hi all,
This study shows improvements in patients with CFS using amino acids.
They discuss the mitochondria and ATP. They state that the patients in the study had elevated lactate levels and that "Blood lactate levels are elevated in CFS patients [5], indicating suboptimal aerobic ATP production."
I have had my lactate tested several times and it is always within the reference range.
Yet I know my aeroibc ATP productionis impaired b/c I"m so tired.
Is it possible to have impaired aerobic metabolism and yet normal lactate levels ?
Or is it one of thoee situations where lactate does not easily show up ontests and yet may be elevated in the tissues
Hi, Susan.
Below is a section of a draft paper that I have written that discusses the literature on lactate in CFS. There may be some more recent publications that are not included, because this was written about 3 years ago:
As mentioned above, the normal metabolism of carbohydrates in the cell occurs in two successive stages: aerobic glycolysis (primarily of glucose) in the cytosol of the cell, followed by oxidative phosphorylation in the mitochondria. Normally, the chief product of glycolysis is pyruvate, which is transported into the mitochondria, where it is oxidized by the action of the Krebs cycle (aka citric acid cycle or tricarboxylic acid cycle) together with the respiratory chain (electron transport chain) to form carbon dioxide and water, which are transported out of the mitochondria and eventually out of the body.
If the mitochondria in a cell are dysfunctional, depending on the type and extent of the dysfunction, the cell uses either of two other alternatives for generating needed ATP from carbohydrates:
If both the NADH shuttles and the respiratory chains are intact, the cell can continue to carry on aerobic glycolysis, perhaps at an increased rate, without the second stage involving the Krebs cycle. In this process, the pyruvate continues to be produced, but it is exported to the blood stream. It can then be carried to other organs that are able to oxidize it, and the excess is transported into the liver. The liver performs gluconeogenesis, an energy-requiring process that converts the pyruvate back to glucose, which is returned to the blood, completing what is called the Cori cycle.
If either the NADH shuttles or the respiratory chains cannot handle the flow of NADH coming from glycolysis, the cell can resort to the less efficient anaerobic glycolysis and can increase the rate of glycolysis. In anaerobic glycolysis, NADH chemically reduces pyruvate to lactate (lactic acid). The resulting lactic acid builds up intracellularly as well as in the extracellular fluid surrounding the cells, and it is also transported into the bloodstream. Its fate from that point on is similar to that of pyruvate, completing the Cori cycle.
In principle, lactic acid can be measured instrumentally using nuclear magnetic resonance techniques, either directly using proton nuclear magnetic resonance spectroscopy (referred to as MRS), or by its effect on the intracellular pH which can be detected using phosphorus-31 nuclear magnetic resonance spectroscopy (referred to as NMR). Both methods have been used in CFS patients, the first in magnetic resonance spectroscopy studies of the brain, and the second in skeletal muscle studies. Lactic acid can also be chemically analyzed in biopsy specimens, and this approach has been used in skeletal muscle tissue in CFS.
Finally, blood samples can be analyzed for lactic acid. It should be noted, however, that the lactic acid levels in the blood are subject to some variability depending on two major factors. The first is the rate of production, which will depend on the degree to which a given patients cells are utilizing anaerobic glycolysis. The second is the rate of removal of lactic acid from the blood, both by organs capable of oxidizing it, such as the heart can normally do, and by gluconeogenesis in the liver. The rate of the latter will depend on the state of the patients hypothalamus-pituitary-adrenal (HPA) axis function, because cortisol from the adrenals normally regulates this rate. It is known that the HPA axis exhibits various degrees of dysfunction in PWCs (86). The rate of gluconeogenesis in some PWCs may also be increased as a result of adaptation to long-term elevated production of lactic acid.
Because of these complexities, in addition to the overall heterogeneity of the CFS population, the evaluation of mitochondrial carbohydrate metabolism by lactic acid measurements should be expected to show considerable variability from one PWC to another, and in fact, this is observed, as will be seen below.
An interesting feature of the Cori cycle is that there is no sink for glucose within this cycle. If a PWC continued to consume carbohydrates and there were no mechanism for disposing of the excess glucose, diabetes mellitus would soon ensue. However, so long as the endocrine pancreas continues to function normally (which must usually be the case in CFS, given that comorbidity of CFS and diabetes mellitus is rare), it will raise its insulin secretion to the degree necessary to induce the liver and adipose cells to import the excess glucose and convert it to stored fat (triglycerides). In a 3-hour oral glucose tolerance test on children with CFS, it was found that the blood glucose level was significantly higher than in controls, and the insulin level was significantly higher during the last half of the test, suggesting that glucose was not being metabolized normally in these children (Miike, 2004).
It seems likely that mitochondrial dysfunction could be responsible by this mechanism for the large, rapid weight gains experienced by many PWCs after onset of CFS. If more carbohydrates are consumed, digested and absorbed than the dysfunctional population of mitochondria are able to oxidize, weight gain will ensue. In many cases such consumption has been reported to be driven by strong cravings for carbohydrates, perhaps in response to the hypoglycemia that can result from poor control of the blood glucose level (Verillo and Gellman, 1997). To our knowledge, a precise study of the occurrence of obesity in CFS has not been performed. However, in a study of 51 female CFS patients from the Wichita epidemiological survey (Fukuda criteria), it was found that 41 % were obese (Vollmer-Conna et al., 2006). For an approximate comparison, the rate of obesity in women in the general population of the U.S. was steady at slightly over 33% for the period between 1999 and 2004 (Ogden et al., 2006). In a longitudinal study of 100 patients with unexplained chronic fatigue over 1.5 years, it was found that the average body mass index increased significantly over time (Schmaling et al., 2005).
It also seems likely that the elevated cholesterol and triglyceride levels seen in many PWCs result from this inability to utilize glucose completely by oxidative metabolism, since, if the excess glucose is not oxidized to carbon dioxide and water, and if it is not excreted in the urine as a result of diabetes mellitus, it can ultimately go only into synthesis of cholesterol and triglycerides, via glucose 6-phosphate and acetyl-CoA. Laboratory tests on 273 CFS patients (175 women, 98 men, average age 41.3 years, Holmes criteria) and 72 healthy controls (40 women, 32 men, average age 47.3 years) showed significantly elevated triglycerides, a lower level of HDL cholesterol, and a lower ratio of HDL to total cholesterol in the blood serum of the CFS patients compared to controls (De Lorenzo et al., 1998).
We will now explore the evidence for mitochondrial dysfunction that comes from evaluation of lactic acid levels. First we will review the studies that evaluated either pH or lactic acid level directly in skeletal muscles:
A phosphorus-31 NMR study on the forearm muscles under exercise in one patient who suffered from prolonged post-viral exhaustion and excessive fatigue showed early intracellular acidosis, suggesting excessive lactic acid formation (Arnold et al., 1984). This would be consistent with mitochondrial dysfunction.
Another phosphorus-31 NMR study under exercise was performed on the forearm muscle flexor digitorum superficialis of 46 CFS patients (22 women, 24 men, mean age 36, history of viral-type illness followed by incapacitating fatigue) and 19 healthy controls (Barnes et al., 1993). No significant differences in pH regulation were seen in the groups when averaged together. However, in 12 of the 46 CFS patients, the relationship between pH and phosphocreatine utilization during exercise fell outside the normal range (See ATP and Creatine Phosphate, below). Of these, 6 showed increased acidification relative to phosphocreatine utilization, and 6 showed reduced acidification. This suggested that there were subgroups with mitochondrial dysfunctions within the group studied.
A third phosphorus-31 NMR study was performed during graded dynamic exercise to exhaustion as well as recovery, on the gastrocnemius muscle of 22 CFS patients (16 women, 6 men, average age 34, all but one meeting Holmes criteria) and 21 normal controls (Wong et al., 1992). The researchers found that there was a marked decrease in pH at peak exercise that was quantitatively equal in the PWCs and the controls, but that it occurred significantly earlier in the PWCs. This indicated that the muscle in the PWCs resorted to anaerobic metabolism significantly earlier, which would be consistent with mitochondrial dysfunction in them.
Another phosphorus-31 NMR study was performed during rest, exercise and recovery on the tibialis anterior muscle of 7 CFS patients (Holmes criteria) and 7 healthy controls (Kent-Braun et al., 1993). Significant differences in pH were not found between the two groups. The number of subjects studied may have been too small to show significant differences, in view of the heterogeneity of the CFS population.
A phosphorus-31 NMR study was also performed before and after exercise on the forearm muscles of 19 CFS patients (15 women, 4 men, aged 25 to 54, Oxford criteria) and 13 sedentary controls (Lane et al., 1998). The researchers found no difference in the pH at rest, but after exercise the intracellular pH in 10 of the CFS patients was significantly lower than that in the other 9 CFS patients and in the controls, again perhaps indicating a subset of CFS patients having mitochondrial dysfunction.
Jones and Heigenhauser reported that many patients with CFS had undergone standardized exercise testing in their laboratory over the previous 30 years, and that a small proportion had shown severe reductions in V (dot) O2 max. with evidence of lactate production at low levels of power output (Jones and Heigenhauser, 2002). They specifically reported on their study of two male CFS patients, aged 26 and 35, who satisfied Fukuda et al. criteria. At the end of 15 minutes of submaximal steadystate exercise, muscle biopsy coupled with chemical analysis showed lactate levels of 33 and 148 millimoles per kilogram of dry weight, compared to 13 +/-5.8 millimoles per kilogram of dry weight in control subjects. These results would be consistent with mitochondrial dysfunction.
In summary, the measurements of lactate levels and resulting pH decreases within muscles during exercise show that there may be a subset of PWCs in whom the rise in lactate and the fall in pH occur sooner than in controls, and are greater in magnitude. This is evidence of mitochondrial dysfunction.
There have also been studies in which lactic acid levels were measured in the blood plasma. Here is a review of them:
An aerobic work capacity study with on-line gas analysis and blood sampling was performed on 13 CFS patients (10 women, 3 men, average age 34, Holmes criteria) and 13 normal controls (Riley et al., 1990). There were three increasing stages of exercise intensity between rest and peak exercise on a treadmill. It was found that the CFS patients had a significantly higher blood lactate concentration at Stage III exertion, compared to the controls.
Lane and a variety of colleagues performed a series of studies involving subanaerobic exercise testing in which they measured blood lactate levels at the beginning, end and 30 minutes after a 15-minute exercise session at 90% of their anaerobic threshold. If the lactate level exceeded the upper 99% reference limit for normal control subjects at two or more ot these times, the patient was judged to be subanaerobic threshold exercise test positive (SATET+). In the first study (Lane et al., 1995), they tested 96 consecutive patients (55 women, 41 men, Oxford criteria), and found that 31 of them (19 women, 12 men) or 32% were SATET+. In the second study (Lane et al., 1998), they added an additional 21 patients to the original group, for a total of 105 patients (57 women, 48 men, Oxford criteria), Of this larger group, 38 out of 105 (or 37%) were found to be SATET+. In the third study (Lane et al., 2003), they tested 48 CFS patients (22 women, 26 men, average ages 37.5 and 35.3 years, respectively, Oxford criteria). In this group, they found that 28 of the 48 patients (or 58.3%) were SATET+.
An ultra-endurance cyclist who developed CFS (male, age 37, Oxford criteria) was given incremental cycle exercise tests before he developed CFS and after he had developed it (Rowbottom et al., 1998). Among other parameters the blood lactate concentration was measured and was found to be significantly higher at all workload levels after he developed CFS.
Another study involved testing of 66 CFS patients (49 women, 17 men, mean age 37.2 years, Oxford criteria, recruited through a fatigue clinic at a general hospital department of psychiatry) and 30 sedentary controls (Fulcher and White, 2000). They were given a treadmill exercise capacity test. The CFS patients were found to have significantly lower blood lactate levels than the controls at both submaximum effort and peak effort.
In a study of 33 CFS patients (17 women, 16 men, mean ages 34.2 and 34.4 years, Fukuda criteria) and 33 controls, stationary cycle incremental exercise to volitional exhaustion was executed (Sargent et al., 2002). Blood plasma lactate was measured at rest, in the last 30 seconds of each 2-minute workload, and every minute for 10 minutes postexercise. No significant difference were found in lactate levels between the PWCs and the controls.
Another group studied 31 CFS patients (22 women, 9 men, aged between 22 and 64 years, Fukuda criteria) and 31 controls (Wallman et al., 2004). They performed a submaximal cycle test (to 0.75 of their individual age-adjusted maximum heart rate or as close as they could come to it) each week for 4 weeks, and results of several parameters were averaged. It was found that the two groups had the same resting blood lactate level, but that the net blood lactate level after exercise was significantly lower for the PWCs than for the controls.
Another exercise study was carried out on 15 CFS patients (6 women, 20 men, mean age 48 years, Fukuda criteria) and 11 healthy sedentary controls (Jammes et al., 38). They performed incremental cycling exercise until exhaustion. Among other parameters, venous blood pH and lactate were measured at rest, at the anaerobic threshold, at peak oxygen uptake and during rest after exercise. The time course of the pH and lactate did not differ between the PWCs and the controls, and the peak lactate variations were the same in the two groups.
In another study, 20 women with CFS and 20 sedentary controls were given a graded exercise test to maximal exertion (VanNess et al., 2007). Plasma lactate was measured before and after the test. No significant difference was found between the PWCs and the controls.
In summary of the blood plasma lactate studies, there were three studies that found no difference between PWCs and controls, two that found lower lactate in the PWCs, and five studies (three of them by the same principal author) that found higher lactate in a subset of PWCs than in the controls. This lack of agreement likely results from the heterogeneity of the CFS population as well as the particular factors that can cause differences in blood lactate levels, as discussed above. Nevertheless, there is still evidence here suggesting that there may be mitochondrial dysfunction in a subset of PWCs.
There have also been studies that measured the level of lactate in the brain, using proton magnetic resonance spectroscopy. These studies have reported elevations in ventricular lactate in cerebrospinal fluid in at least some PWCs relative to controls. One of them involved 31 PWCs (Fukuda criteria), and found elevated ventricular lactate in 20 % of them (Levine et al., 2004). Another included 16 PWCs (Fukuda criteria) and 16 controls (Neustadt et al., 2007). This study showed significantly elevated ventricular lactate in the PWCs relative to the controls (348% higher). These researchers also found that the lactate levels were positively correlated with fatigue severity. These studies provide evidence of mitochondrial dysfunction in the brain in CFS.
Taken together, the studies described in this section present considerable evidence for abnormalities in carbohydrate metabolism in the skeletal muscles and the brain in at least subsets of PWCs, and these abnormalities can be attributed to mitochondrial dysfunction.
Best regards,
Rich
... I have a thread here on aminos too ... This is the same article I have a link to in this thread ... I was hoping it wasn't .... Did you notice that this study was done back in 1994 ? I wonder if there have been any more studies on aminos and CFS since then ? BTW .. these are still helping me with my energy level as long as I take them every few hours.