de Salles Painelli V, Alves VT, Ugrinowitsch C, et al. Creatine supplementation prevents acute strength loss induced by concurrent exercise. Eur J Appl Physiol 2014;114(8):1749-55.del Favero S, Roschel H, Artioli G, et al. Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance. Amino Acids 2012;42(6):2299-305. View abstract.
Longer rest periods are more ideal for making progressive tension overload happen, and shorter rest periods are more ideal for generating metabolic fatigue. So, if you’re doing an exercise that is better suited for progressive overload (i.e. primary compound exercises), you’re going to want to rest longer between sets to maximize strength output. And if you’re doing an exercise that is better suited for metabolic fatigue (i.e. isolation exercises), you’re going to want to rest less between sets to make that happen. And if you’re doing an exercise that is suited equally for a combination of the two (i.e. secondary compound exercises), you’re usually going to want a moderate rest period somewhere in between.
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Minor liver lesions (grade I, no grade II or III, pathology not indicative of toxicity) have been studied in SOD1 G93A transgenic mice (a research model for amyotrophic lateral sclerosis or ALS, but used in this study to assess a state of chronic pro-oxidative stress) for 159 days with 2% of feed intake and in CD-1 rats (seen as normal) over 56 days with 0.025-0.5mg/kg in CD-1 mice, although in Sprague-Dawley rats (normal controls) there were no significant differences noted even after 2% of feed intake for 365 days. These observations appear to be due to the strain of the rodents used, and human studies on amyotrophic lateral sclerosis (ALS; what the SOD1 G93A transgenic mice are thought to represent) lasting from nine to sixteen months with subjects supplementing with up to 10g of creatine daily have failed to find any abnormalities in serum biomarkers of liver or kidney health.
In humans, studies that investigate links between serotonin and creatine supplementation find that 21 trained males, given creatine via 22.8g creatine monohydrate (20g creatine equivalent) with 35g glucose, relative to a placebo of 160g glucose, was found to reduce the perception of fatigue in hot endurance training, possibly secondary to serotonergic modulation, specifically attentuating the increase of serotonin seen with exercise (normally seen to hinder exercise capacity in the heat) while possibly increasing dopaminergic activity (conversely seen to benefit activity in the heat).
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.