madman
Super Moderator
Abstract
Creatine is a nitrogenous organic acid that plays a central role as an energy buffer in high energy demanding systems, including the muscular and the central nervous system. It can be acquired from diet or synthesized endogenously, and its main destination is the system creatine/phosphocreatine that strengthens cellular energetics via a temporal and spatial energy buffer that can restore cellular ATP without a reliance on oxygen. This compound has been proposed to possess secondary roles, such as direct and indirect antioxidant, immunomodulatory agent, and possible neuromodulator. However, these effects may be associated with its bioenergetic role in the mitochondria. Given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have tested the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo animal models are highly encouraging, most clinical trials fail to reproduce positive results suggesting that the prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Nonetheless, the only clearly positive data of the creatine supplementation in human beings are related to the (rare) creatine deficiency syndromes. It seems critical that future studies must establish the best dosage regime to increase brain creatine in a way that can relate to animal studies, provide new ways for creatine to reach the brain, and seek larger experimental groups with biomarkers for prediction of efficacy.
Conclusion
Creatine has been widely used as an enhancer of muscular performance since the 1970s. In this review, we addressed its possible effects and functions in human beings, as well as the results that creatine presented as an adjuvant treatment in preclinical models and clinical trials for several diseases. The solid evidence available in the literature considers that the main function of creatine is by far to allow fast regeneration of ATP, in ATP demanding sites, via CK activity. In addition, studies raise a range of possible secondary creatine functions and effects, including direct and indirect antioxidant activity, overall anti-inflammatory effects (with the exception of the airways), and possible neuromodulation of synapses. However, molecular mechanisms remain a matter of debate, and they may be related to the bioenergetic role that creatine has in the mitochondria. It is a consensus that creatine supplementation is safe and has no serious collateral effects, as stated by the official position of the International Society of Sports Nutrition which has also refuted concerns surrounding renal toxicity (Kreider et al. 2017). In this context, and given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have observed the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo experimental models are highly encouraging, most clinical trials fail to reproduce positive results, suggesting that animal models are better to address biological aspects of a possible treatment than to predict clinical efficacy.
Indeed, very few, mainly small pilot studies reported promising functional or neurological improvements by creatine in human beings. Therefore, future studies should first try to establish the best dosage regime to increase brain creatine in a way that can relate to animal studies. In order to avoid the inevitable saturation of SLC6A8 and the poor permeability of the BBB for creatine, di-acetyl creatine ethyl ester, a compound that should cross biological membranes independently of the transporter due to its very high lipophilicity, may represent a promising alternative (Adriano et al. 2018). Furthermore, available data suggests that a prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Therefore, future studies would benefit from biomarkers predictive of efficacy and determination whether baseline bioenergetics status is a significant variable in whether or not creatine supplementation works. To conclude, to this point, the only clearly positive data on human creatine supplementation in neurodegenerative/metabolic diseases concern the (rare) creatine deficiency syndromes, when the enzymes responsible for creatine biosynthesis are impaired
Creatine is a nitrogenous organic acid that plays a central role as an energy buffer in high energy demanding systems, including the muscular and the central nervous system. It can be acquired from diet or synthesized endogenously, and its main destination is the system creatine/phosphocreatine that strengthens cellular energetics via a temporal and spatial energy buffer that can restore cellular ATP without a reliance on oxygen. This compound has been proposed to possess secondary roles, such as direct and indirect antioxidant, immunomodulatory agent, and possible neuromodulator. However, these effects may be associated with its bioenergetic role in the mitochondria. Given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have tested the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo animal models are highly encouraging, most clinical trials fail to reproduce positive results suggesting that the prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Nonetheless, the only clearly positive data of the creatine supplementation in human beings are related to the (rare) creatine deficiency syndromes. It seems critical that future studies must establish the best dosage regime to increase brain creatine in a way that can relate to animal studies, provide new ways for creatine to reach the brain, and seek larger experimental groups with biomarkers for prediction of efficacy.
Conclusion
Creatine has been widely used as an enhancer of muscular performance since the 1970s. In this review, we addressed its possible effects and functions in human beings, as well as the results that creatine presented as an adjuvant treatment in preclinical models and clinical trials for several diseases. The solid evidence available in the literature considers that the main function of creatine is by far to allow fast regeneration of ATP, in ATP demanding sites, via CK activity. In addition, studies raise a range of possible secondary creatine functions and effects, including direct and indirect antioxidant activity, overall anti-inflammatory effects (with the exception of the airways), and possible neuromodulation of synapses. However, molecular mechanisms remain a matter of debate, and they may be related to the bioenergetic role that creatine has in the mitochondria. It is a consensus that creatine supplementation is safe and has no serious collateral effects, as stated by the official position of the International Society of Sports Nutrition which has also refuted concerns surrounding renal toxicity (Kreider et al. 2017). In this context, and given the fundamental roles that creatine plays in the CNS, several preclinical and clinical studies have observed the potential that creatine has to treat degenerative disorders. However, although in vitro and in vivo experimental models are highly encouraging, most clinical trials fail to reproduce positive results, suggesting that animal models are better to address biological aspects of a possible treatment than to predict clinical efficacy.
Indeed, very few, mainly small pilot studies reported promising functional or neurological improvements by creatine in human beings. Therefore, future studies should first try to establish the best dosage regime to increase brain creatine in a way that can relate to animal studies. In order to avoid the inevitable saturation of SLC6A8 and the poor permeability of the BBB for creatine, di-acetyl creatine ethyl ester, a compound that should cross biological membranes independently of the transporter due to its very high lipophilicity, may represent a promising alternative (Adriano et al. 2018). Furthermore, available data suggests that a prophylactic use for neuroprotection in at-risk populations or patients is the most promising field. Therefore, future studies would benefit from biomarkers predictive of efficacy and determination whether baseline bioenergetics status is a significant variable in whether or not creatine supplementation works. To conclude, to this point, the only clearly positive data on human creatine supplementation in neurodegenerative/metabolic diseases concern the (rare) creatine deficiency syndromes, when the enzymes responsible for creatine biosynthesis are impaired
