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Effect of Oral Creatine Supplementation on Human Muscle GLUT4 Protein…
Our study investigated the impact of creatine supplementation on muscle GLUT4 content and glycogen and total creatine concentrations in healthy subjects during 2 weeks of voluntary leg immobilization followed by 10 weeks of rehabilitation training. Our data are the first to show that creatine supplementation prevents the loss of GLUT4 protein during muscle disuse and increases muscle GLUT4 content above normal levels during subsequent rehabilitation. Furthermore, muscle glycogen concentration was increased during the initial stages of the creatine supplementation.
Glucose transport across the plasma membrane is the rate-limiting step for glucose metabolism. Hence, muscle GLUT4 content is a primary determinant of insulin-stimulated muscle glucose uptake and metabolism. Thus, increasing muscle GLUT4 content by transgenic overexpression or by increased contractile activity enhances maximal insulin-stimulated muscle glucose uptake.
Conversely, reducing the content of GLUT4 by GLUT4 knockout, denervation, or aging impairs insulin-mediated muscle glucose uptake. Our data, therefore, suggest that creatine supplementation in humans may increase insulin sensitivity by increasing muscle GLUT4 content.
Over the last decade, substantial evidence has accumulated to show that endurance exercise training elevates muscle GLUT4 content and insulin-stimulated glucose uptake in both healthy[17,20-28] and insulin-resistant muscles.[29,30]
In this respect, the current study shows that in healthy individuals, a low volume (3 weekly sessions) of moderate resistance training (60% of 1 repetition maximum [RM]), in contrast with endurance training (23-26, 28) or daily maximal resistance training, is not a sufficient stimulus to increase muscle GLUT4 content.
Ten weeks of rehabilitation training per se did not increase muscle GLUT4 content above the baseline level (Fig. 1). However, the same training regimen in conjunction with oral creatine supplementation resulted in a marked increase of muscle GLUT4 protein content. In fact, our observations indicate that oral creatine supplementation can probably increase GLUT4 protein content in skeletal musculature independent of exercise training.
In keeping with earlier observations,[17,20-22,31,32] muscle deconditioning by immobilization in the placebo subjects reduced GLUT4 protein content (~20%). Nevertheless, at the end of the immobilization period, GLUT4 content in the creatine group tended to increase by ~10%, which resulted in a 30% difference in muscle GLUT4 between placebo and creatine supplementation in the absence of a training stsore, it is reasonable to conclude that creatine supplementation can increase GLUT4 protein content in human musculature during episodes of either reduced or increased physical activity.
Based on the current knowledge, it is difficult to reveal the molecular basis for the increase in muscle GLUT4 content that occurs during creatine supplementation. It has recently been observed in rats that short-term administration of aminoimidazole-4-carboximide riboside, an AMP-activated protein kinase (AMPK) agonist, increases muscle GLUT4 content.
Creatine administration that increases AMPK activity by decreasing the phosphocreatine-to-creatine ratio may, thus, explain the increase in GLUT4 protein content in the creatine group. And yet, in both groups the phosphocreatine-to-creatine ratio decreased to the same degree during immobilization and remained below the baseline value during the subsequent rehabilitation period.
Furthermore, it has recently been shown that the creatine kinase (CK) and AMPK enzymes colocalize in muscle cells. According to the prevailing opinion, in skeletal muscle, such coupling should serve to suppress muscle AMPK activity by maintaining high local ATP:AMP and phosphocreatine-to-creatine ratios in conditions of cellular stress, such as contractions. If anything, this inhibitory action is enhanced by the increased muscle phosphocreatine concentration established during the creatine supplementation (Table 1).
Thus, evidence for a possible creatine-induced increase in AMPK activity has not been found. Alternatively, there is substantial evidence to suggest that cellular hydration status is an important factor controlling cellular protein turnover, which in muscle cells, excluding the contractile proteins, may involve other proteins important to energy homeostasis, such as GLUT4.
Creatine is cotransported with Na ions across the sarcolemma, which initiates influx of Cl- and water to balance electroneutrality and osmolality. The resulting increase of cell volume may, in turn, act as an anabolic proliferative signal, which involves activation of the mitogen-activated protein kinase (MAPK) signaling cascade that plays a pivotal role in muscle protein synthesis regulation.[37,38]
It is warranted to further explore the possible role of intracellular creatine content in modulating the concerted actions of CK, AMPK, and MAPK in regulating GLUT4 synthesis and degradation in muscle cells.
The bulk of glucose in the human body is stored as muscle glycogen. The presence of a high muscle glycogen concentration, in general, indicates adequate insulin stimulation of muscle glucose uptake and glycogen synthesis. Furthermore, a high muscle glycogen concentration is a prerequisite for optimal endurance exercise performance.
Robinson et al. have recently demonstrated that carbohydrate intake in conjunction with creatine supplementation resulted in greater postexercise muscle glycogen resynthesis than carbohydrate intake alone. Accordingly, in the current study, during the initial 3 weeks of rehabilitation training, muscle glycogen concentration increased by ~30% in the placebo group, whereas a threefold greater increase occurred in the creatine group.
This higher-than-average glycogen level, established by creatine supplementation (>650 mmol/kg DW) (Fig. 2), corresponds with common glycogen levels in young healthy subjects after glycogen “supercompensation”. Given that no dietary instructions were administered to the subjects, our findings suggest that the addition of creatine supplementation to a standard diet may eventually result in a postexercise increment of muscle glycogen concentration similar to that found after a classical carbohydrate-enriched glycogen supercompensation dietary protocol.
Interestingly, after 5 weeks of creatine supplementation, the increase of muscle glycogen content vanished, despite continued creatine supplementation. In fact, during both immobilization and rehabilitation, the pattern of muscle glycogen changes closely mimicked the fluctuations of muscle total creatine content (Table 1) (Fig. 2).
In this respect, Low et al. have provided clear evidence that osmotic swelling of muscle cells is a potent stimulus to muscle glycogen synthesis. The 30 mmol/kg DW increase of muscle total creatine, established after 3 weeks of training in the creatine group, was therefore probably sufficient to induce a degree of cell swelling necessary to enhance insulin-stimulated glycogen synthesis.[40,36]
If such an osmotic trigger mechanism indeed regulates insulin action on glycogen synthesis during creatine supplementation, then the decrease in muscle creatine content beyond 3 weeks of training might also explain the concurrent decrease in the muscle glycogen storage. The mechanism behind the decrease in muscle creatine content during the final stage of the study, despite continued creatine ingestion at a rate presumed to be sufficient for maintaining an elevated muscle creatine content (5 g/day), is unclear.[2,41]
Studies in rats have demonstrated that long-term high-dose creatine feeding induces a downregulation of muscle total Na-creatine cotransporter protein content. In addition, the low creatine transporter content in failing human myocardium has been found to be associated with a decrease in intracellular creatine storage.
In conclusion, the current findings provide strong evidence to suggest that 1) oral creatine supplementation can offset the decline of muscle GLUT4 protein content in skeletal musculature during disuse atrophy, and 2) oral creatine supplementation increases GLUT4 content during subsequent rehabilitation training.
Based on the present findings, it is warranted to evaluate the potential of long-term creatine supplementation as a strategy to prevent or treat disease conditions characterized by peripheral insulin resistance.