Why Oxaloacetate may treat Fatigue

Fatigue after viral infection is rather common, and many patients report long-lasting fatigue after Covid-19 resolution.  In time, the fatigue may develop into a persistent fatigue  also known as “Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS).  Patients with ME/CFS show a different profile of fatigue than is normal.  Exertion causes lasting fatigue that rest does not improve.  Some patients take 2-3 days to recover from exercise.  Cognitively, they can experience brain fog, confusion, forgetfulness, and lack of concentration.  It is not unusual for these patients have anxiety or gloomy mood.

Fatigue patients experience changes in metabolism.  For example, when exercising, ME/CFS patients have elevated blood lactate levels. (1-4)   In contrast, normal control group patients show a reduction in arterial lactate levels with exercise. (4)  In addition, metabolic profiling shows disturbances in glucose processing, particularly in the first step of glycolysis, along with mitochondrial dysfunction.  (5) Also, there appear to be disturbances in converting fatty acids to energy, resulting in catabolism of muscle tissue. (6)

Oxaloacetate, a metabolite in the Citric Acid Cycle and Urea Cycle, may provide some relief to fatigue.  Here are the reasons:

1. Oxaloacetate is significantly lower in the blood plasma of ME/Cronic Fatigue Syndrome patients, (7) something that may be overcome by supplementation with oxaloacetate as a “Medical Food”.
2. Oxaloacetate significantly reduces cellular fatigue in animals. (8)  Here, we will be testing if oxaloacetate reduces fatigue in the participants of this study.
3. Oxaloacetate has been shown to stabilize blood glucose levels. (9, 10)  As glucose is the fuel for our cells, being able to stabilize the fuel supply may help lessen fatigue.
4. Oxaloacetate has been shown to increase glucose uptake into brain cells. (11, 12)  While glucose can fuel our cells, it is only effective if it can be imported into the cells.
5. Oxaloacetate decreases the production of cytosolic lactate and modifies glycolysis. (13)  In ME/Chronic Fatigue Syndrome patients, lactate production is increased.  Oxaloacetate may redirect metabolism to burn glucose in the mitochondria rather than allow it to ferment it in the cytosol, reducing lactate production.
6. Oxaloacetate enhances neuronal bioenergetic fluxes in animal models. (14) This may lead to clearer thinking, or reduction of mental fatigue. "Brain Fog" is a type of mental fatigue that is commonly reported in Post-Covid-19 patients.
7. Oxaloacetate supplementation builds new mitochondria, the power plants of the cells, in animal models. (12) More power plants mean greater ability to produce ATP, and power the body.
8. Oxaloacetate reduces anxiety and depression in human clinical trials. (15)  Anxiety and gloomy mood are often seen intertwined with fatigue.

This Clinical Trial will test Oxaloacetate for the treatment of fatigue, after Covid-19 infection is resolved.  Both mental (brain fog) and physical fatigue will be examined. This clinical trial will not evaluate the use of oxaloacetate on the disease of Covid-19.

References

1.            Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012;25(9):1073-87.

2.            Natelson BH, Vu D, Coplan JD, Mao X, Blate M, Kang G, et al. Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia. Fatigue. 2017;5(1):15-20.

3.            Ghali A, Lacout C, Ghali M, Gury A, Beucher AB, Lozac'h P, et al. Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome. Sci Rep. 2019;9(1):18817.

4.            Lien K, Johansen B, Veierod MB, Haslestad AS, Bohn SK, Melsom MN, et al. Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 2019;7(11):e14138.

5.            Tomas C, Elson JL, Strassheim V, Newton JL, Walker M. The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function. PLoS One. 2020;15(4):e0231136.

6.            McGregor NR, Armstrong CW, Lewis DP, Gooley PR. Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases. Diagnostics (Basel). 2019;9(3).

7.            Germain A, Ruppert D, Levine SM, Hanson MR. Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol Biosyst. 2017;13(2):371-9.

8.            Nogueira L. Acute Oxaloacetate Exposure Enhances Resistance to Fatigue in in vitro Mouse Soleus Muscle. FASEB Journal. 2011;25(1104.5).

9.            Yoshikawa K. Studies on the anti-diabetic effect of sodium oxaloacetate. Tohoku J Exp Med. 1968;96(2):127-41.

10.          Cash A. Oxaloacetic Acid Supplementation as a Mimetic of Calorie Restriction. Open Longevity Science. 2009;3:22-7.

11.          Vidoni ED, Choi IY, Lee P, Reed G, Zhang N, Pleen J, et al. Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients. Alzheimers Dement. 2020.

12.          Wilkins HM, Harris JL, Carl SM, E L, Lu J, Eva Selfridge J, et al. Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet. 2014;23(24):6528-41.

13.          Ijare O, Conway D, Cash A, Baskin D, Pichumani K. CBMT-49. OXALOACETATE ALTERS GLUCOSE METABOLISM IN GLIOBLASTOMA: 13C ISOTOPOMER STUDY. Neuro-Oncology. 2019;21(Supplement_6):vi43-vi4.

14.          Wilkins HM, Koppel S, Carl SM, Ramanujan S, Weidling I, Michaelis ML, et al. Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure. J Neurochem. 2016;137(1):76-87.

15.          Tully L, Humiston J, Cash A. Oxaloacetate reduces emotional symptoms in premenstrual syndrome (PMS): results of a placebo-controlled, cross-over clinical trial. Obstet Gynecol Sci. 2020;63(2):195-204.