In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found evidence that ingesting creatine can dramatically boost the creatine content of the muscle.[non-primary source needed] In the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered creatine phosphate, and determined that creatine is a key player in the metabolism of skeletal muscle. The substance creatine is naturally formed in vertebrates.
In addition to being potentially harmful, some have argued that there is little evidence to indicate any benefit to using bodybuilding protein or amino acid supplements. "In view of the lack of compelling evidence to the contrary, no additional dietary protein is suggested for healthy adults undertaking resistance or endurance exercise". In dispute of this, one more recent meta-analysis concluded that for athletes participating in resistance exercise training and consuming protein supplements for an average of 13 weeks, total protein intake up to 1.6 g per kg body weight per day would result in an increase in strength and fat-free mass, i.e. muscle, but that higher intakes would not further contribute. The muscle mass increase was statistically significant but modest - averaging 0.3 for all trials and 1.0 to 2.0 kg, for protein intake ≥ 1.6 g/kg/day.
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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, 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.
^ Jump up to: a b c Morton RW, Murphy KT, McKellar SR, Schoenfeld BJ, Henselmans M, Helms E, Aragon AA, Devries MC, Banfield L, Krieger JW, Phillips SM (2017). "A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults". Br J Sports Med. 52 (6): bjsports–2017–097608. doi:10.1136/bjsports-2017-097608. PMC 5867436. PMID 28698222.
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.