Mechanism of Action of Creatine
Creatine works by increasing intramuscular phosphocreatine stores, which rapidly regenerates ATP during high-intensity exercise through the reversible phosphorylation reaction catalyzed by creatine kinase. 1, 2
Primary Energy Mechanism
Creatine increases phosphocreatine (PCr) stores in skeletal muscle by approximately 20%, providing the substrate for rapid ATP resynthesis during intense physical activities 1, 2
The creatine kinase enzyme catalyzes the reversible reaction: phosphocreatine + MgADP⁻ + H⁺ ↔ MgATP²⁻ + creatine, allowing immediate energy production when ATP demand exceeds oxidative supply 2, 3
PCr acts as an energy buffer that protects ATP concentrations during muscle contraction, extending the duration of high-intensity activity possible before fatigue 4, 3
The rate of ATP breakdown during intense activity can reach 400 mM/min, far exceeding the maximum oxidative energy supply rate of ~50 mM/min in untrained individuals, making the PCr system critical for bridging this gap 3
Secondary Mechanisms Beyond Energy Buffering
Creatine enhances glycogen resynthesis and storage when co-ingested with carbohydrates, supporting fuel availability for high-intensity aerobic exercise 5
Supplementation may enhance muscle protein synthesis (MPS) and inhibit muscle protein breakdown (MPB), making it potentially beneficial for preventing muscle wasting 2
Creatine reduces inflammation and oxidative stress and has potential to increase mitochondrial biogenesis, though these mechanisms are less well-established 5
PCr stabilizes biological membranes and may protect cells from ischemic damage, decreasing nucleotide loss during intense activity 6, 4
Cellular Communication Role
Creatine kinase communicates energy demand from sites of ATP breakdown to the mitochondria, slowing and attenuating mitochondrial response to changes in energy demand 3
This signaling function is distinct from the buffering role, allowing coordinated metabolic responses during varying exercise intensities 3
Distribution and Storage
Approximately 95% of the body's 120g total creatine is stored in skeletal muscle (in a 70kg male), with 60% as phosphocreatine and 40% as free creatine 7
Supplementation increases total muscle creatine stores, elevating both free creatine and phosphocreatine concentrations available for the energy system 7, 6