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RESEARCH LETTER
Year : 2023  |  Volume : 69  |  Issue : 3  |  Page : 162-163

Reduced tissue creatine levels in patients with long COVID-19: A cross-sectional study


Applied Bioenergetics Lab, Faculty of Sport and Physical Education, University of Novi Sad, Novi Sad, Serbia

Date of Submission27-Jan-2023
Date of Decision14-Mar-2023
Date of Acceptance15-Mar-2023
Date of Web Publication10-May-2023

Correspondence Address:
Prof. S M Ostojic
Applied Bioenergetics Lab, Faculty of Sport and Physical Education, University of Novi Sad, Novi Sad
Serbia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpgm.jpgm_65_23

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 :: Abstract 


Total creatine concentration in the skeletal muscle and brain of long COVID patients were significantly lower when compared to the reference values for the general population, as measured with proton magnetic resonance spectroscopy at 1.5-T in vastus medialis muscle, thalamus, and three bilateral cerebral locations across the white and gray matter.


Keywords: Fatigue, grey matter, myalgia, skeletal muscle, white matter


How to cite this article:
Ranisavljev M, Todorovic N, Ostojic J, Ostojic S M. Reduced tissue creatine levels in patients with long COVID-19: A cross-sectional study. J Postgrad Med 2023;69:162-3

How to cite this URL:
Ranisavljev M, Todorovic N, Ostojic J, Ostojic S M. Reduced tissue creatine levels in patients with long COVID-19: A cross-sectional study. J Postgrad Med [serial online] 2023 [cited 2023 Sep 23];69:162-3. Available from: https://www.jpgmonline.com/text.asp?2023/69/3/162/376634




Creatine is the central high-energy phosphate-storage molecule of muscle and brain tissue. Previous studies suggest various irregularities in creatine metabolism in patients with postviral fatigue syndrome.[1] Here, we evaluated the concentration of creatine in the skeletal muscle and brain of adults suffering from long COVID-19 syndrome and determined the association between tissue creatine levels and the severity of the symptoms of long COVID.

Nineteen adults (n = 19) with evidence of previous SARS-CoV-2 infection, general fatigue that lasted for at least three months, and one or more additional symptoms of long COVID (e.g., problems with memory and concentration, chest pain or tightness, headache, myalgia); free from other pulmonary and cardiovascular conditions were recruited for this cross-sectional study. All participants had suffered a mild to moderate SARS-CoV-2 infection, without requiring hospital admission or respiratory support, or having any neurological impairments during the acute illness. The trial has been conducted at Applied Bioenergetics Laboratory at the University of Novi Sad, from October 2021 to December 2022, after the Institutional Review Board had approved the study protocol (#46-06-03/202A-2). Main outcome measures included the concentration of total creatine (creatine plus phosphocreatine) assessed by a single-voxel proton magnetic resonance spectroscopy (MRS) at 1.5 T in vastus medialis muscle, thalamus, and three bilateral cerebral locations across the white and gray matter, as previously described.[2] The visual analog scales were used to evaluate the severity of disease-related symptoms.

The mean total creatine concentration in the skeletal muscle of long COVID patients was 29.8 ± 6.9 mM (95% confidence interval [CI], from 26.5 to 33.1); the levels were significantly lower (Z test score = - 5.58; P < 0.001) when compared to the reference values for the general population (36.2 ± 5.0 mM).[3] Creatine levels in the thalamus and white and gray matter of long COVID patients have been depicted in [Figure 1]; the average values in all brain structures examined in our cohort were significantly lower (P <0.05) than creatine concentrations in normal volunteers reported in the literature.[4],[5] A significant association was demonstrated between lower muscle creatine levels and more severe myalgia in long COVID patients (r = - 0.53; P = 0.02). No significant relationships were detected between tissue creatine levels and other long COVID-related symptoms (P > 0.05).
Figure 1: The mean concentrations of total creatine (mM) measured with 1.5-Tesla proton MRS across different brain segments in 19 patients with long COVID (light grey); error bars indicate standard deviation. Dark grey columns denote reference values for the general population (References 4 and 5). Asterisk (*) indicates a significant difference at P < 0.05 between long COVID patients and the reference population in total creatine as evaluated with a one-sample Z-test on the population's mean

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We found that long COVID population is characterized by reduced creatine levels in energy-demanding organs, with lower creatine levels in the skeletal muscle linked with severe muscle pain. Creatine depletion could thus be a newly discovered metabolic footprint of long COVID, perhaps as an end result of supraphysiological energy utilization in this perplexing condition. Still, creatine levels reflect the status of skeletal muscle mass which could be affected by age, physical exercise, chronic inflammation, and medication[6]; these factors were not evaluated in this trial which partly limits the interpretation of our findings. Another possible limitation is a relatively small sample size which is partly due to a high cost of proton MRS per patient, time consuming requirements of the procedure, and complex safety protocols, although it provides a gold standard noninvasive technique for analyzing tissue creatine levels. Replenishing creatine in long COVID by exogenous administration could be considered as a possible strategy to correct the deficit and help relieve patients from myalgia in this clinical population. However, a separate randomized controlled trial will have to be conducted in the future to verify this postulation.

Financial support and sponsorship

This work was supported by the Provincial Secretariat for Higher Education and Scientific Research (# 142-451-2597/2021-01/2 and # 142-451- 3176/2022-01).

Conflicts of interest

Professor SM Ostojic serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). He co-owns patent “Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1) and has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development, the Provincial Secretariat for Higher Education and Scientific Research, AlzChem Group AG, ThermoLife International, and Hueston Hennigan LLP. He is the founder of Centram, a biotechnology startup developing and commercializing innovative nutraceuticals that can support and rejuvenate energy metabolism, the gut-brain-muscle axis, and immunity across various health domains. He does not own stocks and shares in any organization. Other three authors M Ranisavljev, N Todorovic, and J Ostojic J declare no conflicts of interest.



 
 :: References Top

1.
Ostojic SM. Diagnostic and pharmacological potency of creatine in post-viral fatigue syndrome. Nutrients 2021;13:503.  Back to cited text no. 1
    
2.
Ostojic SM, Ostojic J, Drid P, Vranes M, Jovanov P. Dietary guanidinoacetic acid increases brain creatine levels in healthy men. Nutrition 2017;33:149-56.  Back to cited text no. 2
    
3.
Bottomley PA, Lee Y, Weiss RG. Total creatine in muscle: Imaging and quantification with proton MR spectroscopy. Radiology 1997;204:403-10.  Back to cited text no. 3
    
4.
Saunders DE, Howe FA, van den Boogaart A, Griffiths JR, Brown MM. Aging of the adult human brain: In vivo quantitation of metabolite content with proton magnetic resonance spectroscopy. J Magn Reson Imaging 1999;9:711-6.  Back to cited text no. 4
    
5.
Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol 1999;277:R698-704.  Back to cited text no. 5
    
6.
Nader GA. Molecular determinants of skeletal muscle mass: Getting the “AKT” together. Int J Biochem Cell Biol 2005;37:1985-96.  Back to cited text no. 6
    


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