The creatine transporter (CrT) is positively regulated by proteins known to be involved in sensing and responding to the cellular energy state, including the mammalian target of rapamycin (mTOR). Upon activation, mTOR stimulates SGK1 and SGK3 to act upon PIKfyve and subsequently PI(3,5)P2 to increase CrT activity. Beyond mTOR, SGK1 also is stimulated by intracellular calcium and a lack of oxygen (ischemia). Because transient ischemia is associated with increased reactive oxygen species (ROS) production after blood flow is restored (reperfusion) it has been hypothesized that muscle contraction may increase creatine uptake through a similar ROS-mediated mechanism.
Creatine ethyl ester increases muscle levels of creatine to a lesser degree than creatine monohydrate. It may also result in higher serum creatinine levels due to creatine ethyl ester being converted into creatinine via non-enzymatic means in an environment similar to the digestive tract. At equal doses to creatine monohydrate, ethyl ester has failed to increase water weight after 28 days of administration (indicative of muscle deposition rates of creatine, which are seemingly absent with ethyl ester).
Though weight training can stimulate the cardiovascular system, many exercise physiologists, based on their observation of maximal oxygen uptake, argue that aerobics training is a better cardiovascular stimulus. Central catheter monitoring during resistance training reveals increased cardiac output, suggesting that strength training shows potential for cardiovascular exercise. However, a 2007 meta-analysis found that, though aerobic training is an effective therapy for heart failure patients, combined aerobic and strength training is ineffective; "the favorable antiremodeling role of aerobic exercise was not confirmed when this mode of exercise was combined with strength training".
One case study on a subject with a methylentetrahydrofolate reductase (MTHFR) 677TT homozygote, a relatively common genetic mutation known as “mild MTHFR deficiency,” which causes mild homocysteinemia, has seen benefits due to creatine supplementation where homocysteine was approximately halved (49% reduction) while CT heterozygotes and CC homozygotes (n=9) were unaffected. Additionally, one rat study suggested a possible role for creatine in reducing homocysteine levels in a model of high uric acid levels (model for end stage renal disease) but this was not replicated when investigated in humans.
To combat steroid use and in the hopes of becoming a member of the IOC, the IFBB introduced doping tests for both steroids and other banned substances. Although doping tests occurred, the majority of professional bodybuilders still used anabolic steroids for competition. During the 1970s, the use of anabolic steroids was openly discussed, partly due to the fact they were legal. In the Anabolic Steroid Control Act of 1990, U.S. Congress placed anabolic steroids into Schedule III of the Controlled Substances Act (CSA). In Canada, steroids are listed under Schedule IV of the Controlled Drugs and Substances Act, enacted by the federal Parliament in 1996.
Once training is resumed under these conditions, there may be little in the way of caloric support to ensure that protein synthesis and muscle growth occurs. Muscle may even begin to cannibalize itself as the body enters into a catabolic state. Even with the best of diets this can sometimes happen if training demands override the nutritional balance or imbalance.
Heath suggests incorporating dropsets into your training routine by immediately decreasing the weight and repping out again to failure. “Dropsets overload the muscle with shorter rest periods and increasing volume which you need to grow,” says Heath. “That overload improves your body’s abilities to utilize more nutrients, natural growth hormone, and natural testosterone into those areas and makes the supplements you take more effective.” Heath’s favorite way to do dropsets is on a pin-loaded machine since it’s faster to switch weights.
Who Makes It: This product is made by Cellucor, a sports and fitness supplement firm best-known for their C4 line of pre-workout supplements. While C4 is their best seller (and a top seller overall), Cellucor also manufactures a wide range of high-quality supplements for a variety of uses. They have been in business for over 15 years and are a trusted name in the fitness community.
Creatine supplementation in the under 18 population has not received a great deal of attention, especially in regards to sports/exercise performance. Despite this, creatine is being supplemented in young, <18 years old, athletes [52,53]. In a 2001 report  conducted on pupils from middle and high school (aged 10 – 18) in Westchester County (USA) 62 of the 1103 pupils surveyed were using creatine. The authors found this concerning for 2 main reasons: firstly, the safety of creatine supplementation is not established for this age group and is therefore not recommended. Secondly, it was speculated that taking creatine would lead on to more dangerous performance enhancing products such as anabolic steroids. It is important to point out that this potential escalation is speculation. Furthermore, a questionnaire was used to determine creatine use amongst this age group and does not necessarily reflect the truth.
In regard to the blood brain barrier (BBB), which is a tightly woven mesh of non-fenestrated microcapillary endothelial cells (MCECs) that prevents passive diffusion of many water-soluble or large compounds into the brain, creatine can be taken into the brain via the SLC6A8 transporter. In contrast, the creatine precursor (guanidinoacetate, or GAA) only appears to enter this transporter during creatine deficiency. More creatine is taken up than effluxed, and more GAA is effluxed rather than taken up, suggesting that creatine utilization in the brain from blood-borne sources is the major source of neural creatine. However, “capable of passage” differs from “unregulated passage” and creatine appears to have tightly regulated entry into the brain in vivo. After injecting rats with a large dose of creatine, creatine levels increased and plateaued at 70uM above baseline levels. These baseline levels are about 10mM, so this equates to an 0.7% increase when superloaded. These kinetics may be a reason for the relative lack of neural effects of creatine supplementation in creatine sufficient populations.