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Scientists reveal how creatine could do more than build muscle, fueling brain resilience, enhancing mood, and supporting cognitive performance through exercise-driven biochemical pathways.
Study: Creatine supplementation and muscle-brain axis: a new possible mechanism? Image credit: Sonis Photography/Shutterstock.com
Creatine supplementation is widely acknowledged for boosting muscular mass and strength and improving exercise performance. A recent review in Frontiers in Nutrition examined its impact on brain and muscle health via the muscle-brain axis.
Introduction
Both the brain and skeletal muscle consume vast amounts of energy during activity. Creatine is a key regulatory molecule in both organ systems, preventing damage during periods of intensive energy demand. It facilitates rapid energy availability in the form of ATP, reduces oxidative stress, and counters inflammation.
What is creatine?
Creatine, or methyl guanidine acetic acid, is a nitrogen-rich molecule produced from amino acids like arginine, glycine, and methionine. It is produced primarily in the liver and brain but can also be obtained from beef, fish, or pork and consumed as a supplement.
Creatine affects multiple cell pathways and has many different effects. The results include greater energy balance, anti-inflammatory effects, muscle hypertrophy, and improved glucose regulation.
Creatine and the muscle-brain axis
Voluntary muscle cells release myokines, signaling proteins that affect distant organs, including the brain. Myokines may act via the muscle-brain axis, influencing brain health and potentially contributing to overall physical performance rather than directly building muscle strength or endurance.
Crossing the blood-brain barrier, myokines stimulate neuronal proliferation, promote the formation of new neural pathways, and improve the efficiency of existing neuronal circuits. Thus, they enhance cognitive performance and suppress unwanted behavioral changes. They also help protect neurons against inflammation and oxidative stress damage, preserving cognitive performance, especially in age-related or disease-related stress.
It is assumed that the muscle-brain axis is a two-way interactive system of communication, involving myokines, especially brain-derived neurotrophic factor (BDNF), cathepsin B, interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), irisin, and lactate. BDNF is a key neurotrophic protein for neurogenesis and neuroplasticity, and improves memory.
Most of the BDNF in the blood comes from the resting brain or during physical exercise. Acute exercise causes BDNF levels to rise over the short term. Myokines affect lipid metabolism, stimulating the conversion of inactive white fat to active brown fat. They also promote bone formation and endothelial function.
Creatine for energy
Creatine enters cells via a transporter molecule. While a third remains free inside the cell, most undergoes phosphorylation to phosphorylcreatine (PCr). This is a source of active phosphate for ADP, converting it to ATP.
This rapid increase in PCr stores within the muscle promotes the fast resynthesis of ATP, supplying quick energy during high-demand activities like sprinting or resistance exercise. This process is most prominent in tissues that require high energy, like muscle, brain, and heart.
Creatine supplementation
When paired with resistance training, creatine supplementation helps increase lean body mass and muscle strength. It improves training adaptation and recovery. These effects could potentially occur by triggering myokine release, thus promoting anabolism in muscle cells.
Creatine regulates the balance between anti-inflammatory and inflammatory responses to strenuous exercise. It may help prevent injury and keep the body temperature stable during exercise.
Apart from directly promoting myokine production, creatine affects other signaling pathways involved in myokine regulation, such as the mTOR pathway. For instance, creatine supplementation increases IGF-1, a growth factor that improves neuronal proliferation and synaptic plasticity.
Creatine-induced enhancements in anaerobic work performance during repeated bouts of high-intensity muscular activity are potentially beneficial in endurance sports that require sudden surges and paced performances. They could also be important in events like track cycling, where a final intensive effort is key to winning.
Notably, lactate is a myokine and the result of anaerobic muscle metabolism. Yet, lactate concentrations did not rise in blood after short-term creatine supplementation. Lactate does promote increased BDNF levels, perhaps because of rising myokine production induced by creatine-linked increases in ATP.
Creatine supplements could also help in neurodegenerative conditions, including Huntington’s or Parkinson’s disease, and may protect the central nervous system against concussion-related damage. Preliminary studies also suggest benefits for maternal health during pregnancy and reductions in depression risk, and the management of age-related muscle weakness is another possible use.
Creatine as a neuroprotective
There is some evidence that creatine is a neurotransmitter. It occurs within synaptic vesicles, where neurotransmission occurs, and appears to influence communication by cortical neurons. Mitochondrial activity in the hippocampal neurons is also enhanced by creatine. This, coupled with its antioxidant activity, ability to reduce oxidative stress, neurodevelopmental effects, and electrophysiological changes, suggests that creatine may have a neuroprotective effect.
Creatine supplementation supports more intense training, stimulating the release of BDNF and other myokines. Creatine acts indirectly on the brain, through myokines, via its role as a source of quick energy.
Creatine influences the exercise-dependent secretion of neurotransmitters and cytokines like serotonin and dopamine, which improve neural function and promote neuroplasticity. It is also key to emotional regulation, suggesting that creatine could alleviate depression.
Some evidence indicates that creatine has a rapid antidepressant effect via myokine-related pathways, with or without cognitive behavioral therapy. In a recent pilot trial, 5 g/day creatine combined with CBT over 8 weeks produced greater reductions in depression scores than CBT alone, though larger trials are still needed.
Creatine as a metabolic regulator
Creatine supplements improve glucose metabolism by enhancing insulin sensitivity. Insulin directly affects the levels of important myokines acting on the muscle-brain axis. It promotes GLUT-4-mediated glucose uptake into voluntary muscle cells, potentially increasing myokine release in response to exercise.
Conclusions
Creatine supplementation is closely related to physical exercise and increased myokine production. Creatine impacts not only muscle performance but also brain health and cognitive function. It may help prevent inflammatory damage in the muscles and promote recovery from exercise training and depression. However, variability in study design, dosage, and individual responses means that these effects must be interpreted cautiously, and more clinical studies are required to confirm whether creatine directly raises BDNF or other myokine levels.
Multiple biologically relevant pathways can explain how creatine is linked to BDNF, including increased PCr availability or the upregulation of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Alpha (PGC-1α) in skeletal muscle during exercise, which causes irisin and then BDNF levels to rise.
Other factors could include increased creatine-dependent calcium levels and mTOR activation in the muscle cells. However, the effect of creatine supplementation on BDNF and other myokine levels remains unknown. Such research might confirm creatine supplementation’s physical and mental health benefits via the muscle-brain axis.