Testosterone supplementation upregulates androgen receptor expression and translational capacity during severe energy deficit

• Published in: American journal of physiology: endocrinology and metabolism 2020-10, Vol.319 (4), p.E678-E688
• Main Authors: Howard, Emily E, Margolis, Lee M, Berryman, Claire E, Lieberman, Harris R, Karl, J Philip, Young, Andrew J, Montano, Monty A, Evans, William J, Rodriguez, Nancy R, Johannsen, Neil M, Gadde, Kishore M, Harris, Melissa N, Rood, Jennifer C, Pasiakos, Stefan M
• Format: Article
• Language: English
• Subjects: Adaptation; Adolescent; Adult; Androgen receptors; Androgens; Body Composition; Deposition; Diet; Dietary supplements; Energy; Energy Metabolism - drug effects; Exercise; Fibroblast growth factors; Gene expression; Growth factors; Hormones - blood; Humans; Inflammation; Interleukin 6; Interleukin 6 receptors; Male; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscles; Protein Modification, Translational - drug effects; Proteins; Proteolysis; Rapamycin; Receptors; Receptors, Androgen - biosynthesis; Receptors, Interleukin-6 - metabolism; Ribonucleic acid; RNA; Signaling; Skeletal muscle; Testosterone; Testosterone - pharmacology; TOR protein; Translation; TWEAK Receptor - metabolism; Up-Regulation; Young Adult
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00157.2020

Testosterone supplementation during energy deficit promotes whole body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before, 1 h, and 6 h after exercise and a mixed meal (40 g protein, 1 h postexercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active nonobese men treated with 200 mg testosterone enanthate/wk (TEST) or placebo (PLA) during the ED. Participants ( = 10/group) exhibiting substantial increases in leg lean mass and total testosterone (TEST) were compared with those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 gene expression was lower in TEST vs. PLA during ED relative to WM ( < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA ( < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.