key: cord-0961759-lns8to8n
authors: Marshall, Robert Percy; Droste, Jan-Niklas; Giessing, Jürgen; Kreider, Richard B.
title: Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review
date: 2022-01-26
journal: Nutrients
DOI: 10.3390/nu14030529
sha: 88da8becd12813cd03a247a52fd7bc1e98247cd9
doc_id: 961759
cord_uid: lns8to8n

Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.

Creatine (N-aminoiminomethyl-N-methyl glycine) is a naturally occurring and nitrogen containing compound synthesized from the amino acids glycine, methionine that is classified within the family of guanidine phosphagens [1, 2] . About one half the daily need for creatine is obtained from endogenous synthesis while the remaining is obtained from the diet, primarily red meat, fish, or dietary supplements [3, 4] . Creatine is mainly stored in the muscle (95%) with the remaining found in the heart, brain, and testes [3] [4] [5] [6] , with about 2/3 in the form of PCr and the remaining as free creatine [4, 5, 7] . The metabolic basis of creatine in health and disease has been recently reviewed in detail by Bonilla and colleagues [1] (see Figure 1 ). Briefly, adenosine triphosphate (ATP) serves as the primary source of energy in most living cells. Enzymatic degradation of ATP into adenosine diphosphate (ADP) and inorganic phosphate (Pi) liberates free energy to fuel metabolic activity. However, only a small amount of ATP is stored in the cell. Energy derived from the degradation of phosphocreatine (PCr) serves to resynthesize ADP and Pi back to ATP to maintain cellular function until glycolysis in the cytosol and oxidative phosphorylation in the mitochondria can produce enough ATP to meet metabolic demands. Creatine also plays an important role in shuttling Pi from the mitochondria into the cytosol to form PCr to help maintain cellular bioenergetics (i.e., Creatine Phosphate Shuttle) [8] . In this way, PCr can donate its phosphate to ADP, thereby restoring ATP for cellular needs leaving creatine in the cytosol Figure 1 . General overview of the metabolic role of creatine in the creatine kinase/phosphocreatine (CK/PCr) system [1] . The diagram depicts connected subcellular energy production and cellular mechanics of creatine metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum (mitochondrial interactosome and oxidative metabolism), phosphagen and glycolytic system (extramitochondrial ATP production), the linker of nucleoskeleton and cytoskeleton complex (nesprins interaction with microtubules, actin polymerization, β-tubulins), motor proteins (e.g., myofibrillar ATPase machinery, vesicles transport), and ion pumps (e.g., SERCA, Na + /K + -ATPase). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality. Several proteins of the endoplasmic reticulum-mitochondria organizing network (ERMIONE), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na + /Cl − -dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology pro-Numerous studies over the last three decades have shown that creatine monohydrate (CrM) supplementation (e.g., 4 × 5 g/day for 5-7 days or 3-6 g/day for 4-12 weeks) increases muscle creatine and PCr content by 20-40% [5, [11] [12] [13] [14] [15] ] and brain creatine content by 5-15% [16] [17] [18] [19] [20] [21] . Creatine monohydrate supplementation has been reported to safely improve high-intensity exercise performance by 10-20% leading to greater training adaptations in adolescents [22] [23] [24] [25] [26] , young adults [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] , and older individuals [21, [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] . No clinically significant side effects have been reported other than a desired weight gain [49] . Additionally, there is little to no evidence that CrM causes anecdotal reports of bloating, gastrointestinal distress, disproportionate increase in water retention, increased stress on the kidneys, increased susceptibility to injury, etc. [49, 50] . In fact, studies directly assessing whether creatine causes some of those issues found no or opposite effects. As a result, there has been interest in assessing whether CrM supplementation may benefit a number of clinical populations including conditions that impair mitochondrial function [6] . The rationale is that since CrM supplementation can increase high-energy phosphate availability and also has antioxidant, neuroprotective, anti-lactatic, and calcium-homoeostatic effects, increasing phosphagen availability may help improve cell survival and/or health outcomes in conditions in which mitochondrial function is compromised (e.g., ischemia, injury, and/or non-communicable chronic diseases). The purpose of this review is to examine the literature related to the role of CrM supplementation in the management of various conditions characterized by mitochondrial dysfunction and make recommendations about further work needed in this area.

The methodological basis of this narrative review is a selective literature search in the PubMed database, supplemented by a free Internet search (German and English). In a first explorative step, the search terms "creatine supplementation" and/or "mitochondrial dysfunction" and "creatine" and/or "mitochondrial disease" were used. After a first analysis of the searched literature identifying 68 articles, a new selective literature search was performed in the sources described above using the terms mentioned above, adding relevant cited sources and cross-references. Subsequently, titles, abstracts and finally fulltext articles were examined by the scientific team with regard to the suitability of the articles in terms of content and, in a subsequent step, in terms of quality. After the qualitative criteria had been verified, the content exploration was carried out following thematic questions related to the role of creatine in context: (1) Ergogenic role in mitochondrial dysfunction; (2) Noncommunicable chronic diseases (NCD); (3) Cardiovascular disease and ischemic heart failure; (4) Traumatic and ischemic CNS injuries; (5) Neurodegenerative disorders; (6) Psychological disorders; and (7) Chronic Fatigue Syndrome, Post Viral Fatigue Syndrome and Long COVID.

Although there is not clear definition of mitochondrial dysfunction, it generally refers to conditions that reduce the ability of the mitochondria to contribute to production of energy in the form of ATP. However, any alteration of normal mitochondrial function could be called "mitochondrial dysfunction" as well [51] . Mitochondrial dysfunction can be of primary origin through inheriting pathological altered mitochondrial DNA (mtDNA) or acquiring secondary dysfunction through aging and exposure to mtDNA damaging processes [52, 53] . This can be due to traumatic ischemic (blood deficient) or anoxic (oxygen deficient) as well as chronic conditions. Most common reasons for mitochondrial dysfunction are hypoxia, overexpression of reactive oxygen species (ROS), and an alteration of the intracellular calcium homoeostasis. Since creatine supplementation increases the availability of PCr, it may help cells withstand ischemic challenges and/or offset energy deficits associated with mitochondrial dysfunction 3.1. Acute, Traumatic Mitochondrial Dysfunction Figure 2 shows the schematic sequence of an acute traumatic mitochondrial dysfunction with possible subsequent ischemia. The mechanical forces of injury result in an influx of calcium, potassium, and sodium. A calcium gradient is created, which reduces mitochondrial function [54, 55] . In addition, an injury can lead to short-term ischemia (hypoxia) due to swelling, edema formation, development of neuroinflammation, obstruction of vessels, or hemorrhage [56] . The resulting oxygen deficiency interrupts the respiratory chain in the mitochondria. In both cases, the cell must switch to the energetic emergency plan and produce energy glycolytically, thereby increasing lactate production [57-61]. Oxygen radicals are generated, causing oxidative stress. This leads to cell damage and ultimately to cell death (apoptosis) [62-64]. If sufficient creatine phosphate reserves are present, the cell can compensate short-term energy deficits. ATP-dependent calcium transporters can counteract the calcium gradient under consumption of ATP and PCr, maintain the cell milieu, and thus normalize mitochondrial function [65, 66] . Oxygen radicals can be intercepted [67] . Even transient hypoxia of a few seconds can be counteracted by the body in this way [68] . There is evidence that creatine and cyclocreatine inhibit the mitochondrial-creatine kinaseadenine nucleotide translocator (Mi-Cr-ANT) complex and the mitochondrial permeability transition that is associated with ischemic injury and apoptosis [69] . Additionally, creatine enhances the ability of Mi-CK to shuttle ADP for oxidative phosphorylation and PCr formation, thereby decreasing mitochondrial membrane and production of reactive oxygen species (ROS) [70] . Since impairment in cellular energy production and increased oxidative stress are common features in several neuromuscular degenerative diseases, creatine supplementation may provide some therapeutic benefit [69, 70] . In support of this premise, Sakellaris et al. [71, 72] reported that oral administered creatine can be used as an additional supplement in treatment of acute mitochondrial dysfunction after brain injury. These studies showed clear improvement in clinical outcomes of patients with additional creatine-supplementation in comparison to no creatine-intake. Table 1 shows the level of evidence in humans that creatine supplementation may have a positive effect on treatment outcomes in patients with traumatic brain injury. 

Many chronic diseases such as cancer and age-related pathological conditions have been related to an altered mitochondrial function . Chronic mitochondrial dysfunction is usually caused by slow changes in mitochondrial homeostasis eventually leading to an increase in ROS/NOS, glycolysis, and hyper-acidosis. There are multiple factors that directly damage mitochondrial function ( Figure 3 ). Hypoxia is a common factor in conditions such as solid tumor, ischemia, or inflammation that leads to a depletion of oxygen and eventually through production of ROS to an alteration of intracellular proteins, lipids and DNA [89] . On the other hand, research was able to prove that malignant cells tend to create energy under glycolytic conditions although sufficient oxygen is provided. This pathological mechanism is called "Warburg Effect" [102, 103] . This leads to an increase in cell acidity and an increase in ROS with damaging of DNA. Other factors leading to chronic mitochondrial dysfunction are toxic metals or reactive nitrogen species (NOS) [104] . An increase in ingested carbohydrates bigger than the individual needs leads to hyperinsulinemia. As a chronic condition, this will lead to an increase in receptor for advanced glycation end products (RAGE). Thus, nitrosative stress increases, manipulating 

Many chronic diseases such as cancer and age-related pathological conditions have been related to an altered mitochondrial function . Chronic mitochondrial dysfunction is usually caused by slow changes in mitochondrial homeostasis eventually leading to an increase in ROS/NOS, glycolysis, and hyper-acidosis. There are multiple factors that directly damage mitochondrial function ( Figure 3 ). Hypoxia is a common factor in conditions such as solid tumor, ischemia, or inflammation that leads to a depletion of oxygen and eventually through production of ROS to an alteration of intracellular proteins, lipids and DNA [89] . On the other hand, research was able to prove that malignant cells tend to create energy under glycolytic conditions although sufficient oxygen is provided. This pathological mechanism is called "Warburg Effect" [102, 103] . This leads to an increase in cell acidity and an increase in ROS with damaging of DNA. Other factors leading to chronic mitochondrial dysfunction are toxic metals or reactive nitrogen species (NOS) [104] . An increase in ingested carbohydrates bigger than the individual needs leads to hyperinsulinemia. As a chronic condition, this will lead to an increase in receptor for advanced glycation end products (RAGE). Thus, nitrosative stress increases, manipulating mitochondrial function [105] [106] [107] [108] [109] . Increasing stress will lead to an intracellular accumulation of ammonium [110] [111] [112] , ROS [113] , lactate [114] , ultimately inhibiting the Krebs cycle and oxidative metabolism. mitochondrial function [105] [106] [107] [108] [109] . Increasing stress will lead to an intracellular accumulation of ammonium [110] [111] [112] , ROS [113] , lactate [114] , ultimately inhibiting the Krebs cycle and oxidative metabolism. Typical factors that lead to a disturbance in the cellular respiration are hypoxia, inflammation, viruses, mutations, oncogenes, age, radiation, and carcinogens [115] . The ultimate, most common denominators are reactive species which damage mtDNA. As soon as cellular defense systems such as antioxidants, intracellular energetic buffer, and enzymatic reactions are worn down, chronic alteration of cellular organelles begins [116] . As mentioned above, it is hard to differentiate in chronic mitochondrial dysfunction whether pathological conditions lead to hypoxia that produces ROS/NOS which eventually harms mtDNA or whether an altered mtDNA leads to an overexpression of ROS/NOS damaging itself [117] . It is widely accepted, however, that this chronic status is a vicious circle leading to a lethal cellular condition harming the host.

Magnetic resonance spectroscopy (MRS) is an analytical tool that detects electromagnetical signals that are produced by the atomic nuclei within the molecules. Thus, it can be used to (non-invasively) measure concentrations for specific molecules in tissue. This technique has extensively been used in neurological research to identify phosphorus and proton metabolites in tissue in vivo [118] [119] [120] [121] . Using this, research was able to prove mitochondrial dysfunction in patients with bipolar disorders. These patients also suffered from an impaired energy production [122] , increased levels of lactate (hyperacidotic state) [123] and PCr concentration [114, 124, 125] . Therefore, it was assumed that creatine supplementation could improve clinical outcome in cases of mitochondrial dysfunction. Creatine is able to buffer lactate accumulation by reducing the need for glycolysis [126] , reducing ROS [127] and restoring calcium homeostasis. Table 2 presents an overview of the level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction. Typical factors that lead to a disturbance in the cellular respiration are hypoxia, inflammation, viruses, mutations, oncogenes, age, radiation, and carcinogens [115] . The ultimate, most common denominators are reactive species which damage mtDNA. As soon as cellular defense systems such as antioxidants, intracellular energetic buffer, and enzymatic reactions are worn down, chronic alteration of cellular organelles begins [116] . As mentioned above, it is hard to differentiate in chronic mitochondrial dysfunction whether pathological conditions lead to hypoxia that produces ROS/NOS which eventually harms mtDNA or whether an altered mtDNA leads to an overexpression of ROS/NOS damaging itself [117] . It is widely accepted, however, that this chronic status is a vicious circle leading to a lethal cellular condition harming the host.

Magnetic resonance spectroscopy (MRS) is an analytical tool that detects electromagnetical signals that are produced by the atomic nuclei within the molecules. Thus, it can be used to (non-invasively) measure concentrations for specific molecules in tissue. This technique has extensively been used in neurological research to identify phosphorus and proton metabolites in tissue in vivo [118] [119] [120] [121] . Using this, research was able to prove mitochondrial dysfunction in patients with bipolar disorders. These patients also suffered from an impaired energy production [122] , increased levels of lactate (hyperacidotic state) [123] and PCr concentration [114, 124, 125] . Therefore, it was assumed that creatine supplementation could improve clinical outcome in cases of mitochondrial dysfunction. Creatine is able to buffer lactate accumulation by reducing the need for glycolysis [126] , reducing ROS [127] and restoring calcium homeostasis. Table 2 presents an overview of the level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction. 

Modern ways of (unhealthy) living like over nutrition, exposure to toxic substances, and sedentarism combined with an individual's genetic background led to the development of NCD [90] . Four disease clusters are associated with NCD such as cardiovascular diseases, cancers, chronic pulmonary diseases, and diabetes mellitus [129] . NCD are associated with low-grade inflammation and an increase in oxidative stress [130] . Through the past decades, they have become the biggest health threat of modern society [131] [132] [133] . Lately, there has been a link established between NCD and mitochondrial dysfunction. Reduced oxygen consumption rates have been shown in cardiovascular diseases such as hypertension and atherosclerosis. Additionally, they suffer from calcium overload due to mitochondrial calcium mishandling and ROS overproduction [134] [135] [136] [137] . Obesity [138] [139] [140] [141] as well as diabetes mellitus [142] [143] [144] [145] [146] [147] [148] [149] are associated with an increased mitochondrial fragmentation rate, impaired ATP production, as well as ROS overproduction and calcium mishandling. In regards to creatine and its connection to mitochondrial dysfunction, reduced levels were detected in human myocytes in diabetes mellitus [150] , obesity [151] , and hypertension [152] . Not surprisingly, NCD are the most common factors contributing to the development of an acute ischemic heart attack or acute ischemic brain disease ( Figure 4 ). 

Modern ways of (unhealthy) living like over nutrition, exposure to toxic substances, and sedentarism combined with an individual's genetic background led to the development of NCD [90] . Four disease clusters are associated with NCD such as cardiovascular diseases, cancers, chronic pulmonary diseases, and diabetes mellitus [129] . NCD are associated with low-grade inflammation and an increase in oxidative stress [130] . Through the past decades, they have become the biggest health threat of modern society [131] [132] [133] . Lately, there has been a link established between NCD and mitochondrial dysfunction. Reduced oxygen consumption rates have been shown in cardiovascular diseases such as hypertension and atherosclerosis. Additionally, they suffer from calcium overload due to mitochondrial calcium mishandling and ROS overproduction [134] [135] [136] [137] . Obesity [138] [139] [140] [141] as well as diabetes mellitus [142] [143] [144] [145] [146] [147] [148] [149] are associated with an increased mitochondrial fragmentation rate, impaired ATP production, as well as ROS overproduction and calcium mishandling. In regards to creatine and its connection to mitochondrial dysfunction, reduced levels were detected in human myocytes in diabetes mellitus [150] , obesity [151] , and hypertension [152] . Not surprisingly, NCD are the most common factors contributing to the development of an acute ischemic heart attack or acute ischemic brain disease (Figure 4) . Table 3 shows some of the studies that have been conducted on creatine supplementation in noncommunicable chronic diseases. Creatine's benefits in physical activity and thus counteracting NCD development have been widely explained [20, [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] . There is, however, substantial evidence for the beneficial effects of supplementation even without combining it with sports. The sole intake of creatine has been able to significantly lower blood lipids such as cholesterol and triglycerides, slow down the development of fatty liver, and lower the HbA1C in human and animal studies, thus improving the clinical outcome and progression of the metabolic syndrome [164] [165] [166] . 

Optimal replenishment of creatine reserves was able (in experimental studies) to slow down disease progression of the other above mentioned NCD and cardiomyopathy. Therefore, creatine supplementation has been identified to be of special therapeutic interest in treatment of cardiovascular diseases and their course [167, 168] . The heart has its own four creatine kinase (CK) isozymes, proving the importance of ensuring filled energy depots [169] . A gradual reduction of myocardial total creatine content has been shown on chronic heart failure in human as well as animal studies [170] [171] [172] [173] . The ratio of PCr/ATP has been defined to better judge myocardial creatine metabolism [174] . Low ratios have been positively correlated with low contractile function, more severe heart failure symptoms, and a higher risk of mortality [175] [176] [177] .

Creatine supplementation in patients with chronic heart failure and similar animal studies have not shown any beneficial effect on clinical outcome, neither on myocardial creatine concentrations [178] [179] [180] . The transmembrane Creatine-Transporter (CrT) seems to be the limiting factor in this matter [181] . Question remains if other creatine-analogues that pass intracellular without the need of CrT might prove of better help in cardiovascular diseases. The energy deficiency resulting from local hypoxia during an ischemic heart attack leads to mitochondrial dysfunction, which in turn can have arrhythmogenic consequences and lead to sudden cardiac death [182] [183] [184] . Therefore, it is not surprising that creatine plays a critical role during a cardiac ischemic event [185, 186] . First in vitro studies allow the hypothesis that saturation of myocardial creatine stores may lead to protection in the event of a transient ischemic attack [49] . In this context, in animal studies, filled ATP stores have a positive inotropic, apoptosis-protective effect and counteract a post-ischemic inflammatory cascade [187] .

Intravenous in vivo administration of phosphocreatine was able to confer significant myocardial protection after bypass surgery [188] , resulting in a reduction in the incidence of ventricular fibrillation and myocardial infarction as well as arrhythmias [189] . The newly developed special form of creatine, cyclo-creatine, deserves special attention. After an oral loading phase prior to elective cardiac interventions (PCI, ACVB, HTX), cyclo-creatine has a similar protective effect against lethal events [183, 187, 190, 191] . However, large-scale human studies have yet to confirm the initial promising results. Table 4 summarizes the level of evidence available on the role of creatine in cardiovascular disease and ischemic heart failure [187] [188] [189] [190] [191] . 

Mitochondrial function and ATP production are crucial for the neuronal survival and excitability [193] . At the same time, however, mitochondrial dysfunction leads to the overproduction of ROS and neuronal apoptosis which is closely related to neurodegenerative diseases and cerebral ischemia [193] [194] [195] [196] [197] . Whereas earlier research mainly focused on mitochondrial bioenergetic roles, new studies have shown the importance of apoptotic signaling, mitochondrial biogenesis, and mitophagy in the development of cerebrovascular disease and stroke. Mitochondrial health is therefore essential for neurological survival and rehabilitation [198, 199] . Reperfusion injury is another acute complication feared by medical doctors involving mitochondria and clinical outcomes [200, 201] . Following reperfusion of the injured brain tissue, excessive ROS and calcium produced under hypoxic conditions are washed in the body's periphery, causing damage on cellular and molecular level [202] . Intracellular calcium deregulation enhances neuronal cell death after stroke, giving the stability of the mitochondrial (calcium) permeability transition pore (mPTP) a special predictive measure [203] .

The acute protective effects of creatine on the central nervous system (CNS) have long been known. Similar to the effect in the myocardium, energy buffering for shortterm hypoxic conditions can be achieved by saturating intracellular PCr. This may lead to protection against ischemia and cell death, as well as calcium gradients created by mechanical stimuli [204] [205] [206] . In animal experiments, researchers were able to show that idiopathically caused brain damage and spinal cord injuries developed to a lesser extent after creatine oral administration [207, 208] . Creatine supplementation also had a positive effect on infarct sizes after insult in ischemic mouse models [209] . These results suggest that creatine administration may lead to preventive CNS protection against concussions, traumatic brain injury, spinal cord injury, and insults [210] .

Adding to the above-mentioned protective effects of Creatine during a hypoxic situation, special advantages of creatine on the CNS have been proven. The term excitotoxicity describes the destruction of neuronal cells due to pathological activation of its excitatory receptors [202] . Research was able to show that excitatory amino acids, such as Glutamate, become more neurotoxic when the cell's energy levels are reduced by hypoxia [211] . Activation of the glutamate NMDA receptor correlates with reduced ATP and PCr levels [212] . Creatine was able to protect animal brain tissues from the apoptotic effects of excitatory amino acids [213, 214] . Lastly, it was shown that Creatine stabilizes mPTP in rodent studies, thus protecting brain tissue from apoptosis and cell death [67] . Table 5 presents a summary of the level of evidence related to creatine supplementation for traumatic and ischemic CNS injuries [205] [206] [207] . 

Ageing has been defined as a "progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death" [215] . Brain tissue is due to its high-energy demands especially vulnerable to mitochondrial deficits, ROS, hypoxia, and energy depletion [216, 217] . Although ROS are of special need to neurons and brain tissue needed for synaptic plasticity, learning and memory function, their overproduction is closely related to nitration of proteins, mtDNA impairment and the development of neurodegenerative diseases, ageing, and cognitive deficits [218] [219] [220] . Insulin resistance and diabetes mellitus deteriorate these conditions and accelerate cognitive decline as well as incidence of neurogenerative diseases [221] [222] [223] . RAGE and ammonium level up the documented damage to mitochondria, neuronal cells, and brain tissue [224] [225] [226] . Alzheimer's disease has already been named "type 3 diabetes" [227] . Pathologically altered mitochondria have been shown to be swollen, have altered membrane potential, and reductions of ATP levels [228] . Therefore, mitochondrial protection and reduction of oxidative stress have been suggested to be of high therapeutic importance for the treatment of neurodegenerative disorders [229] . Anti-inflammatory nutrition, caloric restriction, as well as the use of supplements have been discussed to be improve mitochondrial functioning and cognition [230] [231] [232] [233] . Various studies have also shown that creatine supplementation has a positive effect on cognition and brain function [234, 235] . The effect was greater the more the participant was exposed to external stressors (e.g., hypoxia, sleep deprivation, etc.) [45, 205] or the more complex the tasks were performed [236] . In this context, intake led to a lower need for sleep, earlier wake-up times, and improved sleep behavior [237] .

Neurodegenerative diseases are usually characterized by the destruction or dysfunction of neurons in a specific brain area. Depending on the affected brain area, course, and severity, the forms of the disease differ. These include Alzheimer's disease (MA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (MH), and Parkinson's disease (MP). Impaired energy balance with mitochondrial dysfunction and oxidative stress are common to all diseases [238] . Similar findings have been made with intellectual disability-related diseases [239] . This bioenergetic deficit is thought to lead to apoptosis and necrosis and ultimately to neuronal degeneration [240] . Therefore, it is reasonable to assume that an improvement in mitochondrial health could enable a positive influence on the course of the disease. Table 6 provides a summary of the level of evidence related to the role of creatine supplementation for neurodegenerative disorders [45, 234, 236] . Initial studies suggest that creatine supplementation may be neuroprotective. For example, in 2013, Kley and coworkers [241] conducted a Cochrane review on the role of creatine monohydrate supplementation for treating muscle disorders. The researchers found sound evidence from randomized clinical trials that creatine supplementation increased strength and functional capacity in muscular dystrophy and idiopathic inflammatory myopathy while having no effect in patients with metabolic-related myopathies and McArdle disease. More long-term research is needed to evaluate the long-term effects of creatine in neurodegenerative diseases that impair muscle function. 

In the 1980s, a link was established between bioenergetic deficits and depression [190, [242] [243] [244] , bipolar disorders [114, 245, 246] , and obsessive-compulsive disorders [247, 248] . It is believed that there is an increase in energy demand with depletion of PCr stores at the onset of disease [124, 249] . In clinical trials with depressed patients [250] [251] [252] , a positive effect on subjective impairment after adjuvant creatine supplementation could be demonstrated. The higher the increase in cerebral PCr after creatine supplementation, the lower the depressive or manic symptoms [253] . The combination of antidepressants and creatine was more effective than simple pharmacological medication [254] . Creatine administration was even effective when drug therapy with SSRIs proved to be ineffective [255] . In this content, creatine has also been discussed as a potential therapeutic agent in the treatment of drug addiction and its psychic related disorders [256] . Positive effects of creatine supplementation have also been reported in post-traumatic stress disorders [257] . Schizophrenic and stress patients seem to gain no benefit from creatine intake. There is, however, ongoing debate on higher dosage for a needed benefit in these sub-groups [258] . Table 7 presents a summary of the literature related to the effects of creatine supplementation on individuals with psychological disorders [251, 252, 255] . 

Fatigue is the most characteristic symptom of an energy deficit. There does not, however, exist a proper definition of the fatigue syndrome [259] . Fibromyalgia is a similar pathological entity closely related to CFS. Initially thought to be purely a psychological problem, linking fatigue to depression or other psychiatric diseases, newer research has been able to prove a metabolic dysfunction causing the symptoms [99, 260, 261] . Linking this clinical state with mitochondrial dysfunction was first able when lowered mitochondrial ATP levels were shown using MRS on patients with fatigue syndrome [262] . Later muscle biopsies and serum biomarkers have been able to show reduced mitochondrial biomarkers [263, 264] . These markers have been Carnitine and CoQ10 [265] . On a mitochondrial level fatty acid metabolism was altered, electron transport chain was disrupted, there was a greater need in glucose concentrations and higher levels of lactate were shown [266] . Higher creatinine excretion via urine was shown to correlate positively with fatigue and pain severity. Being the end product of creatine, this urine marker could imply a higher turnover and depletion of the body's creatine storage [267] . More recent hypotheses state that these alterations have been caused by an activation of immune-inflammatory pathways due to viral infections (e.g., Epstein Barr, Q Fever, Ross River Infection) [268] .

Long COVID is a persistent fatigue state after Sars-2-CoV-2 infection [269, 270] . Interestingly, even asymptomatic patients exhibited raised biomarkers involved in inflammation and stress response [271] . Long COVID, Chronic Fatigue Syndrome, and Post Viral Fatigue Syndrome are believed to be the same entity [248, 272] . Supplementation of guadinioacteic acid, a precursor of creatine, was able to attenuate several aspects of fatigue in fibromyalgia patients [273] . In combination of experimental findings as well as these first promising clinical outcomes, creatine might be an important key in the rehabilitation process of CFS and Long COVID patients [274] . Table 8 summarizes the available literature on the effects of the creatine precursor GAA on chronic fatigue and Post-COVID syndrome [274] . 

This review summarizes creatine's impact on mitochondrial function besides restoring ATP-storage. Creatine monohydrate is one of the best-known nutrient supplements mainly being used for improvement of athletic performance. However, there is growing evidence for a broader therapeutic spectrum of this nitrogen-amino-compound. Various healthpromoting effects on cell-metabolism after the intake of creatine have been shown. Its impact on mitochondrial integrity has become of special interest. Mitochondrial dysfunction has become a central pathological hallmark of non-communicable diseases. The supplementation of creatine monohydrate may have some synergistic effects in the treatment of CND. This seems to be directly related to its protective effects on mitochondria. Different from pharmaceutical products, the intake of creatine is safe age-and gender-independent with nearly no side-effects [49, 50] . Although these findings are promising, much of the available data has been generated with in vitro or animal studies. Therefore, there is a need to conduct more clinical trials in humans to assess the potential therapeutic effects of creatine monohydrate supplementation on conditions influencing mitochondrial function. 

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Chapter One-Oxidative Stress: Love and Hate History in Central Nervous System

Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases

Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors

Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases

Energy demands in competitive soccer

Ammonium metabolism in humans

Ammonia metabolism in exercise and fatigue: A review

Mitochondrial Dysfunction and Mitochondrial Dynamics-The Cancer Connection

Mitochondrial dysfunction in bipolar disorder: Evidence from magnetic resonance spectroscopy research

Warburg Effect-a Consequence or the Cause of Carcinogenesis?

Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies

Evidence of Oxidative Stress and Secondary Mitochondrial Dysfunction in Metabolic and Non-Metabolic Disorders

Introduction to nuclear magnetic resonance

Magnetic resonance spectroscopy

Proton and multinuclear magnetic resonance spectroscopy in the human brain at ultra-high field strength: A review

Magnetic resonance spectroscopy in vivo

Neuronal pathology in the hippocampal area of patients with bipolar disorder: A study with proton magnetic resonance spectroscopic imaging

Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy

Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS

Beyond muscles: The untapped potential of creatine

Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience

Short-term creatine supplementation decreases reactive oxygen species content with no changes in expression and activity of antioxidant enzymes in skeletal muscle

Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state? Free Radic

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study

Measuring the Global Burden of Disease

Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Compromised mitochondrial remodeling in compensatory hypertrophied myocardium of spontaneously hypertensive rat

Accelerated Mitochondrial Adenosine Diphosphate/Adenosine Triphosphate Transport Improves Hypertension-Induced Heart Disease

Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology

Mitochondrial Complex III ROS Regulate Adipocyte Differentiation

Differential alterations in mitochondrial function induced by a choline-deficient diet: Understanding fatty liver disease progression

Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease

Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans

Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation

Mitochondrial H 2 O 2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans

Alteration in mitochondrial Ca2 + uptake disrupts insulin signaling in hypertrophic cardiomyocytes

Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance

The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells

Drp1 guarding of the mitochondrial network is important for glucosestimulated insulin secretion in pancreatic beta cells

Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients

Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes

Effects of catecholamine stress on diastolic function and myocardial energetics in obesity

Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism

The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10

Creatine Supplementation Associated or Not with Strength Training upon Emotional and Cognitive Measures in Older Women: A Randomized Double-Blind Study

Variables Influencing the Effectiveness of Creatine Supplementation as a Therapeutic Intervention for Sarcopenia

Creatine supplementation and resistance training in vulnerable older women: A randomized double-blind placebo-controlled clinical trial

Effects of long-term low-dose dietary creatine supplementation in older women

Impact of creatine supplementation in combination with resistance training on lean mass in the elderly

Exploring the therapeutic role of creatine supplementation

Strategic creatine supplementation and resistance training in healthy older adults

Dietary protein and exercise for preservation of lean mass and perspectives on type 2 diabetes prevention

Nutrition Interventions in Heart Failure

Potential of Creatine in Glucose Management and Diabetes

Creatine in type 2 diabetes: A randomized, double-blind, placebo-controlled trial

High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women

Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: A burden of one-carbon and fatty acid metabolism

Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure

Creatine Kinase System in Failing and Nonfailing Human Myocardium. Circulation

The Failing Heart-An Engine Out of Fuel

The fall in creatine levels and creatine kinase isozyme changes in the failing heart are reversible: Complex post-transcriptional regulation of the components of the CK system

The creatine kinase energy transport system in the failing mouse heart

Decreased Energy Reserve in an Animal Model of Dilated Cardiomyopathy

Augmentation of Creatine in the

31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure

Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease

Myocardial Phosphocreatine-to-ATP Ratio Is a Predictor of Mortality in Patients with Dilated Cardiomyopathy

Chronic high-dose creatine feeding does not attenuate left ventricular remodeling in rat hearts post-myocardial infarction

Effect of creatine supplementation on cardiac muscle of exercise-stressed rats

Regulation of mitochondrial uncoupling respiration during exercise in rat heart: Role of reactive oxygen species (ROS) and uncoupling protein 2. Free Radic

The creatine kinase system as a therapeutic target for myocardial ischaemia-reperfusion injury

Myocardial energy restoration of ischemic damage by administration of phosphoenolpyruvate during reperfusion. A study in a paracorporeal rat heart model

Creatine and cyclocreatine effects on ischemic myocardium: 31P nuclear magnetic resonance evaluation of intact heart

Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies

Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease

Reduced Inotropic Reserve and Increased Susceptibility to Cardiac Ischemia/Reperfusion Injury in Phosphocreatine-Deficient Guanidinoacetate-N-Methyltransferase-Knockout Mice

Enhancement of the recovery of rat hearts after prolonged cold storage by cyclocreatine phosphate

The use of exogenous creatine phosphate for myocardial protection in patients undergoing coronary artery bypass surgery

Reduction of ventricular arrhythmias by phosphocreatine (Neoton) in patients with acute myocardial infarction

Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion

Feeding a creatine analogue delays ATP depletion and onset of rigor in ischemic heart

The Relationship between Plasma BNP Level and the Myocardial Phosphocreatine/Adenosine Triphosphate Ratio Determined by Phosphorus

Magnetic Resonance Spectroscopy in Patients with Dilated Cardiomyopathy

Mitochondrial targeting as a novel therapy for stroke

Mitochondrial targeting for development of novel drug strategies in brain injury

Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival

Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

Mitochondria as a therapeutic target for ischemic stroke. Free Radic

Understanding the Role of Dysfunctional and Healthy Mitochondria in Stroke Pathology and Its Treatment

Molecular Mechanisms of Ischemia-Reperfusion Injury in Brain: Pivotal Role of the Mitochondrial Membrane Potential in Reactive Oxygen Species Generation

A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury

Ischemic stroke and mitochondria: Mechanisms and targets

Mitochondrial calcium function and dysfunction in the central nervous system

The neuropathology and neurobiology of traumatic brain injury

Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation

Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice

Protective effects of oral creatine supplementation on spinal cord injury in rats

Dietary supplement creatine protects against traumatic brain injury

Improved reperfusion and neuroprotection by creatine in a mouse model of stroke

The Effects of Creatine Supplementation and Physical Exercise on Traumatic Brain Injury

Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced

Rapid decrease in ATP content without recovery phase during glutamate-induced cell death in cultured spinal neurons

Preincubation with Creatine Enhances Levels of Creatine Phosphate and Prevents Anoxic Damage in Rat Hippocampal Slices

On the mechanisms of neuroprotection by creatine and phosphocreatine

The aging process

Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer's disease

Mitochondrial dysfunction: The first domino in brain aging and Alzheimer's disease? Antiox. Redox Signal

Neural mechanisms of ageing and cognitive decline

Brain aging and neurodegeneration: From a mitochondrial point of view

Mitochondrial Functioning and the Relations among Health, Cognition, and Aging: Where Cell Biology Meets Cognitive Science

Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia

Alzheimer's Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies

SIRT1 Regulates Cognitive Performance and Ability of Learning and Memory in Diabetic and Nondiabetic Models

The Cerebral Effect of Ammonia in Brain Aging: Blood-Brain Barrier Breakdown, Mitochondrial Dysfunction, and Neuroinflammation

Lores-Arnaiz, S. Brain nitric oxide synthases and mitochondrial function

Mitochondrial dysfunction in acute hyperammonemia

Alzheimer's Disease is Type 3 Diabetes-Evidence Reviewed

Links Between Obesity-Induced Brain Insulin Resistance

Mitochondrial dysfunction: Common final pathway in brain aging and Alzheimer's disease-Therapeutic aspects

The Interaction of Diet and Mitochondrial Dysfunction in Aging and Cognition

Potential for diet to prevent and remediate cognitive deficits in neurological disorders

Oxidative damage and cognitive dysfunction: Antioxidant treatments to promote healthy brain aging

Biochemical deficits and cognitive decline in brain aging: Intervention by dietary supplements

Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal

Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation

Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior

Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats

Cause and consequence: Mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases

Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: An overview of Down syndrome, autism, Fragile X and Rett syndrome

Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases

Creatine for treating muscle disorders

Oxidative Stress at the Crossroads of Aging, Stroke and Depression

The Neurobiology of Anxiety Disorders: Brain Imaging, Genetics, and Psychoneuroendocrinology

Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: A meta-analysis

The role of mitochondrial dysfunction in psychiatric disease

Creatinine and creatine in CSF: Indices of brain energy metabolism in depression. Short note

Increased medial thalamic creatine-phosphocreatine found by proton magnetic resonance spectroscopy in children with obsessivecompulsive disorder versus major depression and healthy controls

Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 "long-haulers"? Chronic Dis

Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression

Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study

Creatine monohydrate in resistant depression: A preliminary study

A randomized, double-blind, placebocontrolled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression

Creatine for the Treatment of Depression

The possible beneficial effects of creatine for the management of depression

Creatine target engagement with brain bioenergetics: A dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression

A potential role for creatine in drug abuse?

Open Study of Creatine Monohydrate in Treatment-Resistant Posttraumatic Stress Disorder

Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neurosci

Fatigue: An overview

Post-Viral Fatigue Syndrome: Evidence for Underlying Organic Disturbance in the Muscle Fibre

Muscle biochemistry and pathophysiology in postviral fatigue syndrome

Heterogeneity in chronic fatigue syndrome: Evidence from magnetic resonance spectroscopy of muscle

Mitochondrial abnormalities in the postviral fatigue syndrome

Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome

Association of mitochondrial dysfunction and fatigue: A review of the literature

Mitochondrial dysfunctions in Myalgic Encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab. Brain Dis

A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls

Viral infection, a suggestive hypothesis for aetiology of chronic fatigue syndrome

Post-viral Fatigue: Implications for Long Covid

Persistent Symptoms in Patients After Acute COVID-19

The long tail of Covid-19'-The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients

COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: A narrative review

Supplementation with Guanidinoacetic Acid in Women with Chronic Fatigue Syndrome

Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome