Based on the limited data on performance and safety, some authors have not identified any conclusions and do not recommend its consumption in regards to creatine supplementation in children and adolescents [52,54]. Conversely, according to the view of the ISSN [5], younger athletes should consider a creatine supplement under certain conditions: puberty is past and he/she is involved in serious competitive training; the athlete is eating a well-balanced caloric adequate diet; he/she as well as the parents approve and understand the truth concerning the effects of creatine supplementation; supplement protocols are supervised by qualified professionals; recommended doses must not be exceeded; quality supplements are administered.
Extracellular creatine (creatine outside of a cell) appears to influence creatine uptake into a cell. It seems that prolonged and excessive levels of creatine actually suppress uptake (a form of negative regulation to prevent excessive influx).[180] In vitro studies in rat muscle cells have shown that including 1mM creatine into cell culture medium substantially reduces creatine uptake into cells. The inhibitory effect was partially negated by protein synthesis inhibitors, suggesting that high levels of creatine induce the expression of a protein that suppresses creatine transporter activity.[180] Similar findings were reported in a later study in cultured mouse myoblasts, which noted a 2.4-fold increase in intracellular creatine levels in the presence of the protein synthesis inhibitor cyclohexamide.[174]

It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio,[333][334] and when activated AMPK (active in states of low cellular energy[335] and colocalizes with creatine kinase in muscle tissue[336]) 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.[334] 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.[334][336][337]


Co-ingesting creatine with caffeine partially negated the benefits of creatine supplementation (at 5mg/kg bodyweight) during the loading phase in one study.[590] The exact mechanism responsible for this effect is not known, but might be related to opposing actions on muscle contraction time.[591] However, another study in trained men found that co-ingestion of 300mg caffeine per day during creatine loading at 20g per day (split into 4 doses) had no effect on bench press 1RM, time to fatigue, or sprinting ability.[592] However, this study also found that creatine alone or when combined with caffeine had no effect on any of these parameters over placebo, either. Thus, the study may have been underpowered or done in too short a time frame (the test was done after only 5 days of loading) to observe any possible effects.[592]
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Creatine supplementation may also be of benefit to injured athletes. Op’t Eijnde et al [39] noted that the expected decline in GLUT4 content after being observed during a immobilization period can be offset by a common loading creatine (20g/d) supplementation protocol. In addition, combining CM 15g/d for 3 weeks following 5 g/d for the following 7 weeks positively enhances GLUT4 content, glycogen, and total muscle creatine storage [39].
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It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio,[333][334] and when activated AMPK (active in states of low cellular energy[335] and colocalizes with creatine kinase in muscle tissue[336]) 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.[334] 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.[334][336][337]
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,[572] yet a later trial trying to replicate the obsevations using 150mg/kg daily for five weeks noted the opposite, that creatine supplementation exacerbated symptoms.[573] 
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