Androgens significantly alter muscle mass in part by shifting protein balance in favor of net protein accretion. During various atrophic conditions, the clinical impact of decreased production or bioavailability of androgens (termed hypogonadism) is important as a loss of muscle mass is intimately linked with survival outcome. While androgen replacement therapy increases muscle mass in part by restoring protein balance, this is not a comprehensive treatment option due to potential side effects. Therefore, an understanding of the mechanisms by which androgens alter protein balance is needed for the development of androgen-independent therapies. While the data in humans suggest androgens alter protein balance (both synthesis and breakdown) in the fasted metabolic state, a predominant molecular mechanism(s) behind this observation is still lacking. This failure is likely due in part to inconsistent experimental design between studies including failure to control nutrient/feeding status, the method of altering androgens, and the model systems utilized.

The metabolic stress placed on skeletal muscle by aerobic exercise promotes acute and long-term health benefits in part through changes in gene expression. However, the transducers that mediate altered gene expression signatures have not been completely elucidated. Regulated in development and DNA damage 1 (REDD1) is a stress-induced protein whose expression is transiently increased in skeletal muscle following acute aerobic exercise. However, the role of this induction remains unclear. Because REDD1 altered gene expression in other model systems, we sought to determine whether REDD1 induction following acute exercise altered the gene expression signature in muscle. To do this, wild-type and REDD1-null mice were randomized to remain sedentary or undergo a bout of acute treadmill exercise. Exercised mice recovered for 1, 3, or 6 h before euthanization. Acute exercise induced a transient increase in REDD1 protein expression within the plantaris only at 1 h postexercise, and the induction occurred in both cytosolic and nuclear fractions. At this time point, global changes in gene expression were surveyed using microarray. REDD1 induction was required for the exercise-induced change in expression of 24 genes. Validation by RT-PCR confirmed that the exercise-mediated changes in genes related to exercise capacity, muscle protein metabolism, neuromuscular junction remodeling, and Metformin action were negated in REDD1-null mice. Finally, the exercise-mediated induction of REDD1 was partially dependent upon glucocorticoid receptor activation. In all, these data show that REDD1 induction regulates the exercise-mediated change in a distinct set of genes within skeletal muscle.

In the absence of androgens, markers of autophagy were elevated, and these could not be normalized by muscle contractions. In the fasted state, REDD1 was identified as a potential contributor to autophagy in noncontracted muscle, whereas phosphorylation of ULK1 may contribute to this process in the contracted muscle. In the refed state, markers of autophagy remain elevated in both noncontracted and contracted muscles, but the relationship with REDD1 and ULK1 (Ser757) no longer existed.

No abstract