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.

Effect of resistance exercise contraction mode and protein supplementation on members of the STARS signalling pathway.

The striated muscle activator of Rho signalling (STARS) pathway is suggested to provide a link between external stress responses and transcriptional regulation in muscle. However, the sensitivity of STARS signalling to different mechanical stresses has not been investigated. In a comparative study, we examined the regulation of the STARS signalling pathway in response to unilateral resistance exercise performed as either eccentric (ECC) or concentric (CONC) contractions as well as prolonged training; with and without whey protein supplementation. Skeletal muscle STARS, myocardian-related transcription factor-A (MRTF-A) and serum response factor (SRF) mRNA and protein, as well as muscle cross-sectional area and maximal voluntary contraction, were measured. A single-bout of exercise produced increases in STARS and SRF mRNA and decreases in MRTF-A mRNA with both ECC and CONC exercise, but with an enhanced response occurring following ECC exercise. A 31% increase in STARS protein was observed exclusively after CONC exercise (P < 0.001), while pSRF protein levels increased similarly by 48% with both CONC and ECC exercise (P < 0.001). Prolonged ECC and CONC training equally stimulated muscle hypertrophy and produced increases in MRTF-A protein of 125% and 99%, respectively (P < 0.001). No changes occurred for total SRF protein. There was no effect of whey protein supplementation. These results show that resistance exercise provides an acute stimulation of the STARS pathway that is contraction mode dependent. The responses to acute exercise were more pronounced than responses to accumulated training, suggesting that STARS signalling is primarily involved in the initial phase of exercise-induced muscle adaptations.