This review paper investigates the relationship between creatine supplementation and the Akt/mTOR pathway, focusing on their impact on muscle performance. The Akt/mTOR pathway is a crucial signaling pathway that regulates muscle protein synthesis and hypertrophy in response to growth factors, nutrients, and mechanical stimuli. Recent evidence suggests that creatine supplementation can influence anabolic signaling pathways, including the phosphorylation of p70S6K, a downstream target of mTOR, leading to enhanced activation of the Akt/mTOR pathway. Additionally, creatine supplementation has been shown to increase intramuscular creatine and phosphocreatine levels, improving ATP availability during exercise and enhancing high-intensity muscle contractions. Understanding the complex regulatory mechanisms of the Akt/mTOR pathway is vital for optimizing muscle performance, as dysregulated signaling can hinder muscle protein synthesis and hypertrophic responses. This review highlights the potential of creatine supplementation to modulate the Akt/mTOR pathway, offering insights into its mechanisms and implications for muscle performance enhancement. By unraveling this connection, researchers and practitioners can develop targeted strategies to maximize muscle performance and promote adaptive responses in various exercise and athletic contexts.

Background and rationale

Muscle performance is a key determinant of athletic prowess, physical fitness, and overall well-being [1-3]. The ability to enhance muscle strength, power, and hypertrophy has long been a pursuit of athletes, bodybuilders, and exercise enthusiasts. In recent years, the Akt/mTOR pathway has emerged as a central regulator of muscle protein synthesis and hypertrophy [4-6]. Activation of this pathway is crucial for the optimization of muscle performance and the adaptive response to exercise stimuli.

Research objectives and aims

The primary aim of this review is to explore the intricate relationship between creatine supplementation and the Akt/mTOR pathway. Creatine supplementation has gained significant attention in the sports and exercise community due to its purported ergogenic effects [7,8]. However, the underlying mechanisms through which creatine influences muscle performance, particularly its interaction with the Akt/mTOR pathway, remain incompletely understood. By synthesizing and analyzing existing literature, this review aims to unravel the connection between creatine supplementation and Akt/mTOR pathway activation, ultimately shedding light on the potential mechanisms by which creatine enhances optimal muscle performance.

Significance of the study

Understanding the link between creatine supplementation and the Akt/mTOR pathway is of paramount importance for athletes, coaches, and sports scientists seeking evidence-based strategies to optimize muscle performance. By elucidating the molecular mechanisms involved, this review aims to contribute to the body of knowledge on how creatine supplementation can enhance the adaptive response of muscle tissue to exercise stimuli. Furthermore, this research has implications beyond the athletic realm, as muscle performance and maintenance play vital roles in overall health, functional independence, and quality of life in diverse populations.

Overview of the Akt/mTOR pathway

The Akt/mTOR pathway is a vital signaling pathway involved in the regulation of muscle performance. It encompasses a complex network of intracellular signaling molecules and pathways that coordinate cellular responses to growth factors, nutrients, and mechanical stimuli [9-11]. Activation of the Akt/mTOR pathway plays a pivotal role in muscle protein synthesis, hypertrophy, and the adaptive response to exercise stimuli [12-14].

Signaling mechanisms of the Akt/mTOR pathway

The Akt/mTOR pathway serves as a crucial signaling cascade that integrates signals from various upstream regulators to coordinate muscle growth and protein synthesis. This pathway is influenced by factors such as growth factors, insulin, and amino acids, which converge to activate and modulate its key components. Among these components, Akt, also referred to as protein kinase B (PKB), occupies a central role as a kinase within the pathway. Activation of Akt is initiated by signaling through phosphatidylinositol 3-kinase (PI3K), leading to its phosphorylation and subsequent activation [14,15]. Once activated, Akt exerts its regulatory function by phosphorylating downstream targets, including the mechanistic target of rapamycin (mTOR). mTOR, in turn, functions as a pivotal regulator of protein synthesis and muscle hypertrophy, exerting control over key cellular processes associated with muscle growth [4,6]

The Akt/mTOR pathway orchestrates the intricate balance between anabolic and catabolic processes within skeletal muscle by serving as a nexus for various signaling inputs. It integrates the signals derived from growth factors, insulin, and amino acids, ultimately coordinating cellular responses and adaptations to exercise stimuli [4,16]. Activation of this pathway triggers a series of molecular events that promote muscle protein synthesis, leading to hypertrophy and the adaptive response to exercise-induced stimuli [4,17,18]. Through its pivotal role in regulating protein synthesis and muscle hypertrophy, the Akt/mTOR pathway emerges as a fundamental mechanism underlying the development and maintenance of skeletal muscle mass and function [4-10].

Role of the Akt/mTOR pathway in muscle protein synthesis and hypertrophy

The Akt/mTOR pathway exerts profound effects on muscle protein synthesis and hypertrophy. Activation of mTOR, a central component of this pathway, triggers a cascade of events that play a critical role in promoting anabolic processes within skeletal muscle [6,19,20]. Upon activation, mTOR phosphorylates downstream targets, including p70S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), which are key regulators of protein translation initiation and ribosomal biogenesis [1,21].

The phosphorylation of p70S6K by mTOR activates its kinase activity, leading to the phosphorylation of ribosomal protein S6 (RPS6) and other downstream targets involved in translation initiation [19]. This activation promotes increased protein synthesis and contributes to the development of myofiber hypertrophy [1,14]. Furthermore, the phosphorylation of 4E-BP1 by mTOR results in its release from eukaryotic initiation factor 4E (eIF4E), allowing eIF4E to initiate translation and enhance the efficiency of protein synthesis [21].

These molecular events orchestrated by the Akt/mTOR pathway ultimately contribute to increased protein synthesis, myofiber hypertrophy, and the development of muscle strength and power [1,18]. This pathway plays a pivotal role in regulating the anabolic processes underpinning muscle growth and adaptive responses to exercise stimuli by modulating the translational machinery and ribosomal biogenesis.

Importance of optimizing the Akt/mTOR pathway for muscle performance

Optimal activation of the Akt/mTOR pathway is crucial for maximizing muscle performance. This pathway plays a central role in coordinating the anabolic processes necessary for muscle protein synthesis, hypertrophy, and adaptive responses to exercise stimuli [13,22].

Deficient or dysregulated signaling within the Akt/mTOR pathway can have detrimental effects on muscle performance. Impaired activation of this pathway may result in reduced muscle protein synthesis, leading to compromised muscle growth and limited gains in strength and power [23,24]. Disruptions in the Akt/mTOR signaling axis can occur through various mechanisms, such as decreased availability of growth factors, alterations in nutrient signaling, or imbalances in cellular energy status [23,24].

Understanding the intricate regulatory mechanisms of the Akt/mTOR pathway is essential for developing strategies to enhance muscle performance and promote muscle adaptations in response to exercise stimuli. Factors that can influence Akt/mTOR signaling include exercise modality, intensity, duration, and nutritional interventions [20,25]. Manipulating these factors in a targeted manner can optimize Akt/mTOR pathway activation and enhance muscle protein synthesis, hypertrophy, and functional outcomes.

By unraveling the complexities of the Akt/mTOR pathway and its regulation, researchers and practitioners can identify novel targets and strategies to optimize muscle performance. This knowledge can inform the development of evidence-based interventions aimed at promoting muscle adaptations and improving athletic performance.

Introduction to creatine supplementation

Creatine supplementation has gained considerable attention as a potential ergogenic aid for enhancing muscle performance. Creatine is a naturally occurring compound synthesized endogenously in the body and obtained from dietary sources. It plays a critical role in energy metabolism, particularly in high-intensity, short-duration activities that rely on the rapid production of adenosine triphosphate (ATP) [26,27].

Biochemical and physiological effects of creatine supplementation

Creatine supplementation is a popular ergogenic aid that has been extensively studied in the context of improving physical performance. Creatine is an organic compound that is naturally produced in the body and is involved in the production of ATP, the primary energy source for muscle contraction. Creatine supplementation has been shown to increase the availability of creatine and its phosphorylated form, phosphocreatine (PCr), in skeletal muscle [28]. This increase in intramuscular creatine and PCr concentrations allows for enhanced ATP availability during high-intensity exercise, which can lead to improvements in muscular power, strength, and endurance [27].

Furthermore, creatine supplementation has been shown to have potential benefits for various populations, including athletes, aging individuals, and those with neuromuscular disorders [28]. In athletes, creatine supplementation has been found to improve performance in sports that require short-term high-intensity efforts, such as weightlifting and sprinting [26]. In older adults, creatine supplementation has been found to enhance muscle mass, strength, and physical function [29]. In individuals with neuromuscular disorders, creatine supplementation has been shown to improve muscle strength and function [30].

Impact of creatine supplementation on muscle strength and power

Numerous studies have demonstrated the positive effects of creatine supplementation on muscle strength and power. Creatine has been shown to enhance muscular force production, improve maximal strength, and increase power output during resistance training and explosive activities [31]. These performance enhancements are attributed to the increased availability of ATP and the potentiation of neuromuscular mechanisms.

Effects of creatine supplementation on endurance performance

In addition to its impact on strength and power, creatine supplementation may also benefit endurance performance. While traditionally associated with high-intensity activities, creatine has shown potential in enhancing repetitive sprint performance, reducing muscle fatigue, and improving work capacity during prolonged endurance tasks [32,33].

Introduction to the Akt/mTOR pathway and muscle adaptations

As discussed in Topic 2, the Akt/mTOR pathway plays a crucial role in muscle protein synthesis, hypertrophy, and the adaptive response to exercise stimuli. In this topic, we will explore the potential link between creatine supplementation and the activation of the Akt/mTOR pathway, shedding light on the molecular mechanisms that may underlie the observed effects of creatine on muscle performance.

Cellular and molecular mechanisms of creatine supplementation

Recent studies have shed light on potential mechanisms by which creatine supplementation may impact the Akt/mTOR pathway. These mechanisms provide insights into the molecular pathways through which creatine supplementation may influence muscle protein synthesis and hypertrophy.

One proposed mechanism involves the upregulation of insulin-like growth factor 1 (IGF-1) expression. Creatine supplementation has been shown to enhance IGF-1 signaling, which can activate the Akt/mTOR pathway and promote muscle protein synthesis [16]. IGF-1 is a potent growth factor that stimulates muscle growth and regulates protein synthesis. By increasing IGF-1 expression or signaling, creatine supplementation may amplify Akt/mTOR pathway activation, leading to enhanced muscle protein synthesis and hypertrophy.

Another potential mechanism involves the modulation of intracellular energy status and ATP availability. Creatine supplementation increases intramuscular creatine and phosphocreatine (PCr) levels, which can enhance cellular energy reserves [34]. This increased energy availability may positively impact the activation of mTOR and its downstream targets involved in protein synthesis. Adequate ATP levels are necessary for optimal mTOR signaling, and by maintaining higher ATP levels, creatine supplementation may support the sustained activation of the Akt/mTOR pathway and promote muscle protein synthesis.

These proposed mechanisms highlight the multifaceted effects of creatine supplementation on the Akt/mTOR pathway. By influencing IGF-1 expression and signaling, as well as intracellular energy status, creatine supplementation may provide a favorable environment for the activation of the Akt/mTOR pathway and subsequent muscle protein synthesis and hypertrophy.

Influence of creatine supplementation on anabolic signaling

Emerging evidence indicates that creatine supplementation can potentially influence anabolic signaling pathways involved in muscle protein synthesis. Several studies have shown that creatine supplementation can lead to increased phosphorylation of p70S6K, a downstream target of mTOR, which suggests enhanced activation of the Akt/mTOR pathway and subsequent effects on protein synthesis and muscle adaptation [16,35,36].

The phosphorylation of p70S6K is an important step in the activation of protein synthesis. By increasing p70S6K phosphorylation, creatine supplementation may facilitate the translation of mRNA into proteins, thereby promoting muscle protein synthesis and hypertrophy. This enhanced activation of the Akt/mTOR pathway can result in an upregulation of key proteins involved in muscle growth and adaptation [13,16,37].

Moreover, another study reported that creatine supplementation augmented the phosphorylation of Akt, a critical kinase that activates mTOR and regulates protein synthesis [38]. Activation of Akt is known to stimulate protein synthesis and muscle growth, and the increased Akt phosphorylation observed following creatine supplementation further supports the notion that creatine may influence the Akt/mTOR pathway.

These findings highlight the potential of creatine supplementation to modulate anabolic signaling pathways involved in muscle protein synthesis. By promoting the phosphorylation of p70S6K and Akt, creatine supplementation may enhance the activation of the Akt/mTOR pathway, leading to increased protein synthesis and muscle adaptation.

Integration of creatine supplementation and Akt/mTOR pathway activation

In previous topics, we explored the effects of creatine supplementation on muscle performance and the potential link between creatine and Akt/mTOR pathway activation. In this topic, we will integrate the evidence and discuss the implications of creatine supplementation for optimizing muscle performance through the activation of the Akt/mTOR pathway.

Enhancing muscle strength and power

Creatine supplementation has consistently shown positive effects on muscle strength and power [31]. By increasing intramuscular creatine and PCr concentrations, creatine supplementation enhances ATP availability during high-intensity, short-duration activities. This improved energy supply contributes to enhanced force production, allowing individuals to generate greater muscle strength and power.

Promoting muscle hypertrophy and adaptation

The activation of the Akt/mTOR pathway is a key regulator of muscle protein synthesis and hypertrophy [32]. By potentially enhancing Akt/mTOR pathway activation, creatine supplementation may facilitate greater muscle protein synthesis, leading to increased muscle mass and hypertrophy. This can have profound implications for individuals seeking to optimize muscle performance and achieve their desired body composition goals.

Accelerating recovery and reducing fatigue

Creatine supplementation has been associated with improved muscle recovery and reduced fatigue. By enhancing energy availability and promoting efficient cellular energy metabolism, creatine may support faster recovery between exercise bouts and attenuate the development of muscle fatigue. This can allow athletes to train at higher intensities and frequencies, ultimately leading to greater gains in muscle performance [33].

Safety and side effects of creatine supplementation

While creatine supplementation is generally regarded as safe for most individuals, it is important to consider potential side effects and address any safety concerns. Commonly reported side effects include gastrointestinal discomfort, muscle cramps, and weight gain. It is crucial for individuals considering creatine supplementation to consult with healthcare professionals and follow appropriate dosing guidelines to minimize the risk of adverse effects [39-41].

Individual variability and response to creatine supplementation

It is worth noting that individual responses to creatine supplementation can vary. Some individuals may experience significant improvements in muscle performance, while others may show minimal or no response. Factors such as genetic variations, baseline creatine levels, training status, and diet may contribute to these individual differences [42]. Future research should aim to identify biomarkers or genetic markers that can help predict an individual’s response to creatine supplementation [43].

Synergistic strategies and combination approaches

Considering the complexity of muscle performance regulation, exploring synergistic strategies and combination approaches may offer further benefits. For example, combining creatine supplementation with resistance training or other nutritional interventions may have additive or synergistic effects on muscle adaptations [27]. Investigating the interplay between creatine supplementation and other ergogenic aids could provide valuable insights into optimizing muscle performance.

Long-term effects and sustainability

While short-term studies have shown promising results, there is a need for long-term investigations to evaluate the sustained effects and safety of creatine supplementation. Longitudinal studies assessing the impact of extended creatine supplementation on muscle performance, body composition, and health parameters are warranted. Additionally, exploring the potential for cycling or intermittent dosing strategies could help mitigate any potential long-term concerns.

Future directions and research gaps

To advance our understanding of the relationship between creatine supplementation, Akt/mTOR pathway activation, and muscle performance, future research should focus on several key areas. These include elucidating the molecular mechanisms underlying the interaction between creatine and the Akt/mTOR pathway, investigating optimal dosing protocols and timing strategies, exploring the effects of creatine supplementation on specific populations (e.g., older adults, females), and assessing the potential for long-term adaptations and health outcomes.

Creatine supplementation is a widely used strategy to enhance muscle performance and has generally been considered safe. However, addressing safety concerns and potential side effects is crucial, including gastrointestinal discomfort, muscle cramps, and weight gain. Consulting healthcare professionals and following appropriate dosing guidelines are important to minimize the risk of adverse effects. Individual responses to creatine supplementation can vary due to factors such as genetic variations, baseline creatine levels, training status, and diet. Future research should aim to identify biomarkers or genetic markers that can help predict an individual’s response to creatine supplementation. Exploring synergistic strategies and combination approaches, such as combining creatine supplementation with resistance training or other nutritional interventions, may provide additional benefits. Long-term investigations are needed to evaluate the sustained effects and safety of creatine supplementation, including its impact on muscle performance, body composition, and health parameters. Understanding the molecular mechanisms underlying the interaction between creatine and the Akt/mTOR pathway, optimizing dosing protocols and timing strategies, assessing the effects of creatine supplementation on specific populations, and exploring long-term adaptations and health outcomes are important areas for future research.

This work would not have been possible without the contribution of the great scientists who made the discoveries described here. I also thank Dr. Marcelo F Costa for his support and encouragement.

Declaration of conflicting interests

The authors declared no potential conflicts of interest concerning this article’s research, authorship, and/or publication.

Consent of publication and funding: The authors received no financial support for this article’s research, authorship, and/or publication.

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