However, if you increase the demands you are placing on your body by increasing the weight being lifted, lifting the same weight for additional reps, or just doing something that increases the demands that your body needs to meet, then your body will have no other choice but to make the changes and improvements necessary for it to adapt to this environment and remain capable of performing these tasks.
In vitro, creatine (0.125mM or higher) can reduce excitotoxicity from glutamate, which is thought to be secondary to preserving intracellular creatine phosphate levels. Glutamate-induced excitotoxicity is caused by excessive intracellular calcium levels resulting from ATP depletion. Since high levels of calcium inside the cell are toxic, ATP preserves membrane integrity, in part by promoting calcium homeostasis. When ATP is depleted, the sodium-potassium ATPase pump (Na+,K+-ATPase) stops working, leading to sodium accumulation in the cell. This reduces the activity of the sodium-calcium exchange pump, which, alongside a lack of ATP, reduces calcium efflux through the Na+,K+-ATPase. Thus, ATP depletion leads to intracellular calcium overload, loss of membrane potential, and excitotoxic cell death. Therefore, by helping preserve ATP levels, creatine is protective against excitotoxicity. This protective effect was noted after either creatine preloading or addition up to 2 hours after excitotoxicity. Protection from glutamate-induced toxicity also extends to glial cells and is additive with COX2 inhibition.
Creatine supplementation has once been noted to improve wellbeing and fatigue resistance in people with DM2, but has twice failed for people with DM1. In all three studies, it has failed to improve power output. This is thought to be due to a reduction in the expression of the creatine transporter preventing an increase in muscular phosphocreatine content.
These effects were noted before in a preliminary study of depressed adolescents (with no placebo group) showing a 55% reduction in depressive symptoms at 4g daily when brain phosphocreatine levels increased. Other prelimnary human studies suggest creatine might lessen unipolar depression and one study on Post-Traumatic Stress Disorder (PTSD) noted improved mood as assessed by the Hamilton Depression Rating Scale.
Creatine has been investigated for its effects on depression, due to the significant changes occurring in brain morphology and neuronal structure associated with depression and low brain bioenergetic turnover in depression, perhaps related to abnormal mitochondrial functioning, which reduces available energy for the brain. The general association of low or otherwise impaired phosphate energy systems (of which creatine forms the energetic basis of) with depression, has been noted previously. Due to associations with cellular death and impaired bioenergetics with depression, creatine was subsequently investigated.
Collectively the above investigations indicate that creatine supplementation can be an effective strategy to maintain total creatine pool during a rehabilitation period after injury as well as to attenuate muscle damage induced by a prolonged endurance training session. In addition, it seems that creatine can act as an effective antioxidant agent after more intense resistance training sessions.