Creatine concentration is normally increased in the placenta and brain in the midgestation phase until term, with further increases in the brain for another two weeks after birth. This effect appears to be due to the fetus itself expressing the creatine enzymes of synthesis (AGAT and GAMT) after 5% of the gestation time has passed (0.9 days in spiny mice). Despite creatine normally suppressing AGAT when supplemented at high concentrations, it appears that maternal supplementation of the diet with 5% creatine from the halfway point of pregnancy until term does not alter creatine synthesis in the newborn (no alterations in either AGAT or GAMT), nor does it affect the creatine transporter.
The maximum amount of creatine the body can store is about 0.3 gram per kilogram of body weight . The creatine content of skeletal (voluntary) muscles averages 125 millimoles per kilogram of dry matter (mmol/kg/dm) and ranges from about 60 to 160 mmol/kg/dm. Approximately 60% of muscle creatine is in the form of PCr. Human muscle seems to have an upper limit of creatine storage of 150 to 160 mmol/kg/dm. Athletes with high creatine stores don't appear to benefit from supplementation, whereas individuals with the lowest levels, such as vegetarians, have the most pronounced increases following supplementation. Without supplementation, the body can replenish muscle creatine at the rate of about 2 g/day .
Osteoblast cells are known to express creatine kinase. Bone growth factors such as IGF-1, PTH, and even Vitamin D seem to induce bone growth alongside increases in creatine kinase activity. Vitamin D has been noted to work indirectly by increasing the cellular energy state (these hormones increase creatine kinase in order to do so) in order to make bone cells more responsive to estrogen. This evidence, paired with enhanced growth rates of osteoblasts in the presence of higher than normal (10-20mM) concentrations of creatine suggest a role of creatine in promoting osteoblastic and bone growth, secondary to increasing energy availability.
In females, the combination of SSRIs (to increase serotonin levels in the synapse between neurons) and creatine shows promise in augmenting the anti-depressive effects of SSRI therapy. Another pilot study conducted on depression and females showed efficacy of creatine supplementation. The one study measuring male subjects noted an increase in mood and minimal anti-depressive effects, but it is not know whether this is due to gender differences or the model studies (post-traumatic stress disorder).
In summary, creatine salts have been show to be less stable than CM. However the addition of carbohydrates could increase their stability . The potential advantages of creatine salts over CM include enhanced aqueous solubility and bioavailability which would reduce their possible gastrointestinal adverse effects . The possibility for new additional formulation such as tablets or capsules is interesting for its therapeutic application due to its attributed better dissolution kinetics and oral absorption compared to CM . However more complete in vivo pharmaceutical analysis of creatine salts are required to fully elucidate their potential advantages/disadvantages over the currently available supplement formulations.
It may seem odd to put such a common supplement as minerals on this list, but few people are aware that minerals are enzyme activators. Many vitamins, on the other hand, are coenzymes, which means that without minerals they're useless. Many minerals, such as zinc and chromium, also interact with various anabolic hormones, such as testosterone, growth hormone and insulin.
In a mouse model of allergin-induced asthma, where mice were sensitized by ovalbumin for three weeks and then given 500mg/kg creatine, supplementation induced an increase in asthmatic hyperresponsiveness to low but not high doses of methacholine. This hyperresponsiveness was associated with increased eosinophil and neutrophil infiltration into the lungs, and an increase in Th2 cell cytokines (IL-4 and IL-5) alongside an increase in IGF-1, which is known to influence this process. Interestingly, there was a nonsignificant increase in responsiveness in mice not sensitized to ovalbumin.
One pilot study using 150mg/kg creatine monohydrate for a five day loading phase followed by maintenance (60mg/kg) for the remainder of the five weeks noted that supplementation was associated with fewer muscle symptoms and complaints alongside improved muscular function, yet a later trial trying to replicate the obsevations using 150mg/kg daily for five weeks noted the opposite, that creatine supplementation exacerbated symptoms.
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.