Low Tissue Creatine: A Therapeutic Target in Clinical Nutrition

Low tissue creatine characterizes many conditions, including neurodegenerative, cardiopulmonary, and metabolic diseases, with a magnitude of creatine shortfall often corresponds well to a disorder’s severity. A non-invasive monitoring of tissue metabolism with magnetic resonance spectroscopy (MRS) might be a feasible tool to evaluate suboptimal levels of creatine for both predictive, diagnostic, and therapeutic purposes. This mini review paper summarizes disorders with deficient creatine levels and provides arguments for assessing and employing tissue creatine as a relevant target in clinical nutrition.publishedVersio

Safety of dietary guanidinoacetic acid: a villain of a good guy?

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy me-tabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an ener-gy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effective-ly increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompetes traditional bioenergetics agents in maintain-ing ATP status druing stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appears to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition, and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision anal-ysispublishedVersio

Malproduction of endogenous hydrogen gas in COVID-19

The molecular footprints of COVID-19 occur everywhere, even reaching the family of biologically active gases and gasotransmitters. Besides nitric oxide and hydrogen sulfide, COVID-19 might also alter the homeostasis of dihydrogen (H2), another gaseous bioactive molecule produced endogenously by the human gut bacteria. Many studies have shown various alterations of the gut microbiota in patients with coronavirus disease 2019, including the lower abundance of hydrogen-producing bacteria that could instigate the shortage of hydrogen output. Since dihydrogen has many important bioactivities, including cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic, its malproduction in COVID-19 might contribute to the disease progression and severity. On the other hand, replenishing dihydrogen by exogenous administration could be beneficial in COVID-19 for both patient- and clinical-reported outcomes. Assessing low dihydrogen along with H2 supplementation to restore normal levels could be thus combined via theranostic approaches to aid COVID-19 diagnosis and treatment

Guanidinoacetic Acid as a Nutritional Adjuvant to Multiple Sclerosis Therapy

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Improving brain creatine uptake by Klotho protein stimulation: can diet hit the big time?

Creatine plays a pivotal role in cellular bioenergetics, acting as a temporal and spatial energy buffer in cells with high and fluctuating energy requirements (1). Jeopardizing delicate creatine homeostasis can be detrimental to many energy-demanding tissues, including the brain. For instance, cerebral creatine hypometabolism accompanies various neurological conditions, including a number of developmental disorders (2, 3), neurodegenerative and cerebrovascular diseases (4, 5), and brain cancer (6). A reduced creatine availability in the brain has been thus recognized as an apposite therapeutic target, and supplying exogenous creatine to compensate for a disease-driven shortfall emerged as a first possible approach. However, early success in animal models of neurological diseases was not corroborated in human trials, with the use of creatine supplementation proved largely disappointing in clinical studies with a number of symptomatic neurological disorders [for a detailed review, see (7)]. A meager delivery of creatine to the brain could be partly due to a low activity/density of creatine transporter (CT1 or SLC6A8), a transmembrane sodium- and chloride-dependent protein that mediates creatine uptake into the target cells (8). For that reason, the upregulation of CT1 function has been identified as an innovative course of action to facilitate creatine uptake, with several exotic agents and routes were cataloged so far, including glucocorticoid-regulated kinases, mammalian target of rapamycin, ammonia, and Klotho protein (9).publishedVersio

Guanidinoacetate–creatine in secondary progressive multiple sclerosis: a case report

Acute secondary progressive multiple sclerosis (SPMS) is characterized by escalating neurological disability, with limited disease-modifying therapeutic options. A 48-year-old woman with acute SPMS being treated with interferon beta-1a and oral corticosteroids presented as a clinical out- patient with no disease-modifying effects after treatment. A decision was made to treat her with a combination of guanidinoacetate and creatine for 21 days. She had made clinical progress at follow-up, with the intensity of fatigue dropping from severe to mild. Magnetic resonance spec- troscopy revealed increased brain choline, creatine, N-acetylaspartate, and glutathione. Patients with SPMS may benefit from guanidinoacetate–creatine treatment in terms of patient- and clinician-reported outcomes; this requires additional study.publishedVersio

Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome

Dietary creatine has been recently put forward as a possible intervention strategy to reduce post-COVID-19 fatigue syndrome yet no clinical study so far evaluated its efficacy and safety for this perplexing condition. In this parallel-group, randomized placebo-controlled double-blind trial, we analyzed the effects of 6-month creatine supplementation (4 g of creatine monohydrate per day) on various patient- and clinician-reported outcomes, and tissue creatine levels in 12 patients with post-COVID-19 fatigue syndrome. Creatine intake induced a significant increase in tissue creatine levels in vastus medialis muscle and right parietal white matter compared to the baseline values at both 3-month and 6-month follow-ups (p < .05). Two-way analysis of variance with repeated measures revealed a significant difference (treatment vs. time interaction) between interventions in tissue creatine levels (p < .05), with the creatine group was superior to placebo to augment creatine levels at vastus medialis muscle, left frontal white matter, and right parietal white matter. Creatine supplementation induced a significant reduction in general fatigue after 3 months of intake compared to baseline values (p = .04), and significantly improved scores for several post-COVID-19 fatigue syndrome-related symptoms (e.g., ageusia, breathing difficulties, body aches, headache, and difficulties concentrating) at 6-month follow-up (p < .05). Taking creatine for 6 months appears to improve tissue bioenergetics and attenuate clinical features of post-COVID-19 fatigue syndrome; additional studies are warranted to confirm our findings in various post-COVID-19 cohorts.publishedVersio

Creatine consumption and liver disease manifestations in individuals aged 12 years and over

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