madman
Super Moderator
Abstract: There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans. There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression). Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, the data available are promising and future research in the area is warranted.
1. Introduction
The ergogenic effects of creatine supplementation are well documented, with evidence supporting its efficacy in increasing muscle strength, lean mass, and exercise performance/muscle function, particularly when combined with exercise in different populations, from athletes to a wide spectrum of patient populations [1–3].
Creatine mechanisms of action involve rapid energy provision by transferring the N-phosphoryl group from phosphorylcreatine (PCr) to adenosine diphosphate (ADP), thus resynthesizing adenosine triphosphate (ATP) and spatial energy buffering, transferring energy from the mitochondria to the cytosol. These mechanisms are responsible for facilitating ATP homeostasis during high energy turnover, maintaining a low ADP concentration and reducing Ca2+ leakage from the sarcoplasmic reticulum, and impairing of force output of the muscle [4–6]. Additionally, creatine could also attenuate the formation of reactive oxygen species by its coupling with ATP into the mitochondria or by scavenging radical species in an acellular setting [7]. Its direct and indirect antioxidant effects have been suggested to have therapeutic effects in neurodegenerative diseases [8].
Although most of the total body’s creatine is found in skeletal muscle, the brain is also a very metabolically active tissue, accounting for up to 20% of the body’s energy consumption [9,10]. Creatine kinase (CK), the main enzyme involved in the ATP/CK/PCr system is also expressed in a brain-specific isoform (BB-CK) [4–6], suggesting that creatine may also be relevant for energy provision to the central nervous system (CNS). In fact, creatine-deficient syndromes involving brain creatine depletion are characterized by major mental and developmental disorders (e.g., mental retardation, learning delays, autism, and seizures), which may be partially reversed by creatine supplementation [11–14]. Cognitive processing may also be affected by creatine metabolism, as it may facilitate ATP homeostasis during periods of rapid or altered brain ATP turnover, such as during complex cognitive tasks, hypoxia, sleep deprivation, and some neurological conditions [3,15,16]. Additionally, creatine supplementation might be beneficial for mild traumatic brain injury (mTBI), which is also associated with changes in brain energy needs. The effects of creatine supplementation on brain creatine levels, cognitive processing, and mTBI have been previously reviewed [3,17,18]. As this is a growing field, the purpose of this short review is to provide an update regarding the effects of creatine supplementation on brain health in humans beyond what is discussed in Dolan et al. [3].
2. The Effects of Creatine Supplementation on Brain Creatine Levels
3. Creatine Supplementation and Cognition
4. Creatine Supplementation and Brain Injury, Concussion, and Hypoxia
5. Conclusions and Future Directions
There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mTBI, aging, Alzheimer’s disease, depression).
However, at least three main gaps remain. First, it is important to determine the optimal creatine protocol able to increase brain creatine levels. So far, dose-response studies are lacking and protocols are heterogeneous. Second, supplementation studies concomitantly assessing brain creatine levels and cognitive function are needed, as it may help establish causation for the effect of creatine supplementation on cognition. Third, the identification of novel conditions in which creatine supplementation may be more effective in improving cognitive function is warranted as creatine in a rested healthy brain has been shown to have a lessened effect.
1. Introduction
The ergogenic effects of creatine supplementation are well documented, with evidence supporting its efficacy in increasing muscle strength, lean mass, and exercise performance/muscle function, particularly when combined with exercise in different populations, from athletes to a wide spectrum of patient populations [1–3].
Creatine mechanisms of action involve rapid energy provision by transferring the N-phosphoryl group from phosphorylcreatine (PCr) to adenosine diphosphate (ADP), thus resynthesizing adenosine triphosphate (ATP) and spatial energy buffering, transferring energy from the mitochondria to the cytosol. These mechanisms are responsible for facilitating ATP homeostasis during high energy turnover, maintaining a low ADP concentration and reducing Ca2+ leakage from the sarcoplasmic reticulum, and impairing of force output of the muscle [4–6]. Additionally, creatine could also attenuate the formation of reactive oxygen species by its coupling with ATP into the mitochondria or by scavenging radical species in an acellular setting [7]. Its direct and indirect antioxidant effects have been suggested to have therapeutic effects in neurodegenerative diseases [8].
Although most of the total body’s creatine is found in skeletal muscle, the brain is also a very metabolically active tissue, accounting for up to 20% of the body’s energy consumption [9,10]. Creatine kinase (CK), the main enzyme involved in the ATP/CK/PCr system is also expressed in a brain-specific isoform (BB-CK) [4–6], suggesting that creatine may also be relevant for energy provision to the central nervous system (CNS). In fact, creatine-deficient syndromes involving brain creatine depletion are characterized by major mental and developmental disorders (e.g., mental retardation, learning delays, autism, and seizures), which may be partially reversed by creatine supplementation [11–14]. Cognitive processing may also be affected by creatine metabolism, as it may facilitate ATP homeostasis during periods of rapid or altered brain ATP turnover, such as during complex cognitive tasks, hypoxia, sleep deprivation, and some neurological conditions [3,15,16]. Additionally, creatine supplementation might be beneficial for mild traumatic brain injury (mTBI), which is also associated with changes in brain energy needs. The effects of creatine supplementation on brain creatine levels, cognitive processing, and mTBI have been previously reviewed [3,17,18]. As this is a growing field, the purpose of this short review is to provide an update regarding the effects of creatine supplementation on brain health in humans beyond what is discussed in Dolan et al. [3].
2. The Effects of Creatine Supplementation on Brain Creatine Levels
3. Creatine Supplementation and Cognition
4. Creatine Supplementation and Brain Injury, Concussion, and Hypoxia
5. Conclusions and Future Directions
There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mTBI, aging, Alzheimer’s disease, depression).
However, at least three main gaps remain. First, it is important to determine the optimal creatine protocol able to increase brain creatine levels. So far, dose-response studies are lacking and protocols are heterogeneous. Second, supplementation studies concomitantly assessing brain creatine levels and cognitive function are needed, as it may help establish causation for the effect of creatine supplementation on cognition. Third, the identification of novel conditions in which creatine supplementation may be more effective in improving cognitive function is warranted as creatine in a rested healthy brain has been shown to have a lessened effect.
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