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In a later study, it was found that biologically relevant concentrations (10-30mM) of creatine bind synthetic membranes with lipid compositions mimicking the inner mitochondrial membrane or plasma membrane in a concentration-dependent manner. This also conferred a degree of protection, increasing membrane stability in response to challenge from a number of destabilizing agents. Phosphocreatine was more effective than creatine in this context, although both were able to bind and stabilize membranes.
In vitro studies on endothelial cells have noted that the benefits of creatine against atherosclerosis (via immune cell adhesion to the endothelial cell) are blocked with the pharmaceutical ZM241385, a high affintiy adenosine A2A receptor antagonist. This particular receptor subset (A2A rather than other adenosine receptors) and its inhibition are similar to caffeine, suggesting that caffeine may have an inhibitory effect on this mechanism of creatine.
If you want to take creatine as a supplement for bigger and stronger muscles, then the standard protocol is to have a “loading period” where you significantly increase your creatine intake for a few days or weeks. “This can prime your muscles to increase the amount of creatine that they ‘hold,’” explains Bates. “During the loading period, you generally take 5 g of creatine four times per day. After the loading period, you decrease the amount of creatine you take to a ‘maintenance’ level of 3 to 5 g per day.” (That’s also the recommendation from the International Society of Sports Nutrition.) (5)
Despite a possible decreasing creatine content in the muscles when maintenance is deemed suboptimal, the overall retention of weight and lean mass is merely additive over time. This is thought to be due to increases in skeletal muscle production (increase in body weight) compensating for the progressive declines in water and glycogen content (decreases in body weight).
When Katula started his research on whether weight training would improve quality of life for seniors, he realized that many had never even picked up a dumbbell. “They first had to learn how to use these big intimidating weights and machines,” he says. He recalls the story of one woman who protested that she couldn’t do the leg press machine. Finally, Katula persuaded her to sit in the machine and set the weight at 50 pounds. “I couldn’t believe how fast she whipped out 10 reps,” he says, “When she got out of that machine, she was two inches taller just from increased pride.”
In regard to bioenergetics, phosphorylated cyclocreatine appears to have less affinity for the creatine kinase enzyme than phosphorylated creatine in terms of donating the high energy phosphate group (about 160-fold less affinity) despite the process of receiving phosphorylation being similar. When fed to chickens, phosphorylated cyclocreatine can accumulate up to 60mM in skeletal muscle, which suggests a sequestering of phosphate groups before equilibrium is reached. Cyclocreatine still has the capacity to donate phosphate, however, as beta-adrenergic stimulated skeletal muscle (which depletes ATP and glycogen) exhibits an attenuation of glycogen depletion (indicative of preservation of ATP) with phosphocreatine.
^ Jump up to: a b c d Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Crit. Rev. Food Sci. Nutr. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass. ... The meta analysis studies and the individual studies conducted support the use of HMB as an effective aid to increase body strength, body composition, and to prevent muscle damage during resistance training.
It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio, and when activated AMPK (active in states of low cellular energy and colocalizes with creatine kinase in muscle tissue) appears to inhibit creatine kinase via phosphorylation (preserving phosphocreatine stores but attenuating the rate that creatine buffers ATP). While phosphocreatine technically inhibits AMPK, this does not occur in the presence of creatine at a 2:1 ratio. It seems that if the ratio of phosphocreatine:creatine increases (indicative of excess cellular energy status) that AMPK activity is then attenuated, since when a cell is in a high energy status, there is less AMP to directly activate AMPK.