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[233]) while possibly increasing dopaminergic activity (conversely seen to benefit activity in the heat[234]).[155]
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]

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.[119]
Glycogen synthesis is known to respond directly and positively to cellular swelling. This was demonstrated in an earlier study, during which rat muscle cells were exposed to a hypotonic solution in vitro to induce cell swelling, which increased glycogen synthesis by 75%. In contrast, exposing these same cells to a hypertonic solution hindered glycogen synthesis by 31%. These changes were not due to alterations in glucose uptake, but are blocked by hindering the PI3K/mTOR signaling pathway.[112] It was later noted that stress proteins of the MAPK class (p38 and JNK) as well as heat shock protein 27 (Hsp27) are activated in response to increasing osmolarity.[113][114] Furthermore, activation of MAPK signaling in skeletal muscle cells is known to induce myocyte differentiation[115] via GSK3β and MEF2 signaling, which can induce muscle cell growth.[116][117]
A thermogenic is a broad term for any supplement that the manufacturer claims will cause thermogenesis, resulting in increased body temperature, increased metabolic rate, and consequently an increased rate in the burning of body fat and weight loss. Until 2004 almost every product found in this supplement category comprised the "ECA stack": ephedrine, caffeine and aspirin. However, on February 6, 2004 the Food and Drug Administration (FDA) banned the sale of ephedra and its alkaloid, ephedrine, for use in weight loss formulas. Several manufacturers replaced the ephedra component of the "ECA" stack with bitter orange or citrus aurantium (containing synephrine) instead of the ephedrine.
Second, strength training has a much greater level of excess post-exercise oxygen consumption than aerobic exercise.  What does this mean?  When you finish a workout, your body needs to do a lot of work to replenish itself in order to bring itself back to a normal state (the way it was before you worked out).  This takes a lot of energy, and some studies have shown that it can boost your metabolism for up to 38 hours after you finish your workout.
Studies measuring extracellular water versus intracellular water note similar increases in both, associated with creatine. Creatine does not tend to disturb the ratios of water to dry mass in various tissues measured.[609] At least one study in older men (48-72 years) has failed to find a significant difference in both intracellular and extracellular water concentration after 14 weeks of 5g creatine daily (with gatorade) relative to gatorade in isolation, with the ratio being maintained.[615]
Key point: Past a certain number of sets, the marginal increases in protein synthesis NO LONGER outweigh the cost of doing more sets. If 8 sets of chest exercises produce 95% of possible muscle protein synthesis… then it makes very little sense to do ANOTHER 10 sets (like most chest workouts) to try and inch out the final 5% of stimulation. Those extra 10 sets are simply damaging your muscle unnecessarily and impairing your ability to recover.
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.[192] In contrast, the creatine precursor (guanidinoacetate, or GAA) only appears to enter this transporter during creatine deficiency.[192] 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[192] is the major source of neural creatine.[193][192] However, “capable of passage” differs from “unregulated passage” and creatine appears to have tightly regulated entry into the brain in vivo[193]. 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.[193] These kinetics may be a reason for the relative lack of neural effects of creatine supplementation in creatine sufficient populations.
×