The current treatment for obesity is a regimen of exercise and forced calorie restriction in order to create a negative energy balance. In the short term such programmes undoubtedly cause weight loss, but much of this weight is now known to be skeletal muscle mass. This is problematic, because loss of skeletal muscle significantly reduces the resting metabolic rate and this change can be almost permanent once initiated. The low resting metabolic rates of those who have undergone such periods of negative energy balance is problematic because it greatly increases the risk of future weight gain and this explains the failure of dieting and exercise to cause successful long term improvements in body composition. Muscle hypertrophy is thought to be stimulated by insulin and insulin-like growth factor-1 (IGF-1), receptors for which are located in high concentrations on skeletal muscle. Forced calorie restriction reduces insulin and IGF-1 concentrations in plasma and this might be the primary driver that leads to the catabolism of muscle tissue.
Both insulin and IGF-1 are thought to bind to receptors in skeletal muscle tissue and activate the transmembrane tyrosine kinase signal pathway linked to protein kinase B (AKT). Activation of the AKT in turn results in increased protein synthesis and inhibition of protein degradation. However, the protein atrophy pathway that can lead to skeletal muscle loss is not a simple reversal of the AKT pathway, but instead results in the activation of other pathways that directly stimulates the atrophy-related genes in the nucleus. The AKT pathway has been investigated in calorie restricted mice, where it was shown that feed deprivation for 10 or 12 hours results in decreases in AKT phosphorylation of 50 and 76 %, respectively in juvenile mice1. In adult mice, deprivation of feeding for 24 hours results in reduced AKT phosphorylation of 70 %. In addition, feeding restriction increased the mRNA levels of muscle RING-finger protein-1 (murf1) and muscle atrophy F-box protein (fbxo32), two proteins involved in the degradation of skeletal muscle.
These results support the hypothesis that insulin and IGF-1 can prevent muscle catabolism through activation of the downstream signal protein AKT, and that food deprivation increases catabolism because the activity of this protein is reduced, while the activity of degradation proteins is increased. In this way the insulin and IGF-1 stimulate the AKT pathways and cause skeletal muscle hypertrophy, whereas calorie restriction inhibits skeletal muscle hypertrophy and allows atrophy to ensue. The AKT protein synthesis pathway is activated through the stimulation of mTOR and this protein can also be activated directly by amino acids transported into the muscle cells. This may go some way to explaining the anti-catabolic effect of high protein diets, which would increase the availability of circulating amino acids for uptake to skeletal muscle. In addition, some amino acids are insulinogenic which means that they would cause the release of insulin and IGF-1, and this too may explain the protein sparing effects of high protein diets.