Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy

Abstract

Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signalling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic targets (glycogen synthase kinase-3beta (GSK-3beta), mTOR, p70(s6k) and 4E-BP1) and catabolic targets (Foxo1, Foxo3, atrogin-1 and MuRF1). All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. Following resistance training a muscle hypertrophy ( approximately 10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content were observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1 were observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signalling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes.

Figure 5. Representative images of Ponceau staining and Tubulin protein content for cytosolic proteins (A) and Ponceau staining and lamin A protein content for nuclear proteins (B)

Figure 1. Percentage change in quadriceps size following 8 weeks of resistance training (Post-Tr) and 8 weeks of de-training (Post-DeTr)

Muscle size was determine using a CT scan as mentioned in the methods section. *significantly different from post-training levels, P < 0.05; **Significantly different from pre-training levels, P < 0.01.

Figure 2. Effect of 8 weeks of resistance training (Post-Tr) and 8 weeks of de-training (Post-DeTr) on the protein content of phospho-Akt, phospho-GSK-3β, phospho-mTOR and Foxo1

*Significantly different from post-training levels, P < 0.05; **significantly different from Pre-training levels, P < 0.01.

Figure 3. Effect of 8 weeks of resistance training (Post-Tr) and 8 weeks of de-training (Post-DeTr) on the protein content of phospo-p70^s6k and phospho-4E-BP1

Figure 4. Regulation of atrogin-1 mRNA and protein as well as MuRF1, Psma1 and UBB mRNA following 8 weeks of resistance training (Post-Tr) and 8 weeks of de-training (Post-DeTr)

*Significantly different from Pre-training and Post-de-training levels (P < 0.05); **significantly different from Pre-training and Post-de-training levels (P < 0.01).