Stec MJ, Kelly NA, Many GM, Windham ST, Tuggle SC, Bamman MM. Ribosome biogenesis may augment resistance training-induced myofiber hypertrophy and is required for myotube growth in vitro. Am J Physiol Endocrinol Metab 310: E652-E661, 2016. First published February 9, 2016 doi:10.1152/ajpendo.00486.2015.-Resistance exercise training (RT) is the most effective method for increasing skeletal muscle mass in older adults; however, the amount of RT-induced muscle growth is highly variable between individuals. Recent evidence from our laboratory and others suggests ribosome biogenesis may be an important factor regulating RT-induced hypertrophy, and we hypothesized that the extent of hypertrophy is at least partly regulated by the amount of RT-induced ribosome biogenesis. To examine this, 42 older adults underwent 4 wk of RT aimed at inducing hypertrophy of the knee extensors (e.g., 2 sets of squat, leg press, and knee extension, 10 -12 repetition maximums, 3 days/wk), and vastus lateralis muscle biopsies were performed pre-and post-RT. Post hoc K-means cluster analysis revealed distinct differences in type II myofiber hypertrophy among subjects. The percent change in type II myofiber size in nonresponders (Non; n ϭ 17) was Ϫ7%, moderate responders (Mod; n ϭ 19) ϩ22%, and extreme responders (Xtr; n ϭ 6) ϩ83%. Total muscle RNA increased only in Mod (ϩ9%, P Ͻ 0.08) and Xtr (ϩ26%, P Ͻ 0.01), and only Xtr increased rRNA content (ϩ40%, P Ͻ 0.05) and myonuclei/type II fiber (ϩ32%, P Ͻ 0.01). Additionally, Mod and Xtr had a greater increase in c-Myc protein levels compared with Non (e.g., approximately ϩ350 and ϩ250% vs. ϩ50%, respectively, P Ͻ 0.05). In vitro studies showed that growth factor-induced human myotube hypertrophy is abolished when rRNA synthesis is knocked down using the Pol I-specific inhibitor CX-5461. Overall, these data implicate ribosome biogenesis as a key process regulating the extent of RT-induced myofiber hypertrophy in older adults. skeletal muscle; ribosome; rRNA; c-Myc; Pol I LOSS OF SKELETAL MUSCLE MASS with aging (i.e., sarcopenia) and disease (e.g., cachexia) is associated with poor clinical outcomes (23, 24) and higher all-cause mortality (44); thus, maximizing mechanisms of muscle regrowth is a high priority. Restoration of muscle mass and contractile function is dependent on an accumulation of various protein pools (myofibrillar, mitochondrial, etc.) within myofibers that leads to overall myofiber hypertrophy. To achieve this, the primary focus to date has been on mechanisms regulating translation initiation. Many have reported acute induction of the relevant signaling pathways in response to various hypertrophy stimuli (protein nutrition, anabolic drugs, exercise) (3, 10, 14, 17, 27, 41), and we have shown that some of these induced signals regulate myofiber hypertrophy (e.g., eIF2Bε) (29). On the other hand, little attention has been given to other potentially rate-limiting processes, including overall ribosomal capacity, which is dependent on efficiency and the number of available ribosomes...