Influence of divergent exercise contraction mode and whey protein supplementation on atrogin-1, MuRF1, and FOXO1/3A in human skeletal muscle.

Knowledge from human exercise studies on regulators of muscle atrophy is lacking, but it is important to understand the underlying mechanisms influencing skeletal muscle protein turnover and net protein gain. This study examined the regulation of muscle atrophy-related factors, including atrogin-1 and MuRF1, their upstream transcription factors FOXO1 and FOXO3A and the atrogin-1 substrate eIF3-f, in response to unilateral isolated eccentric (ECC) vs. concentric (CONC) exercise and training. Exercise was performed with whey protein hydrolysate (WPH) or isocaloric carbohydrate (CHO) supplementation. Twenty-four subjects were divided into WPH and CHO groups and completed both single-bout exercise and 12 wk of training. Single-bout ECC exercise decreased atrogin-1 and FOXO3A mRNA compared with basal and CONC exercise, while MuRF1 mRNA was upregulated compared with basal. ECC exercise downregulated FOXO1 and phospho-FOXO1 protein compared with basal, and phospho-FOXO3A was downregulated compared with CONC. CONC single-bout exercise mediated a greater increase in MuRF1 mRNA and increased FOXO1 mRNA compared with basal and ECC. CONC exercise downregulated FOXO1, FOXO3A, and eIF3-f protein compared with basal. Following training, an increase in basal phospho-FOXO1 was observed. While WPH supplementation with ECC and CONC training further increased muscle hypertrophy, it did not have an additional effect on mRNA or protein levels of the targets measured. In conclusion, atrogin-1, MuRF1, FOXO1/3A, and eIF3-f mRNA, and protein levels, are differentially regulated by exercise contraction mode but not WPH supplementation combined with hypertrophy-inducing training. This highlights the complexity in understanding the differing roles these factors play in healthy muscle adaptation to exercise.