title: mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling.
abstract: Ribosome production is an early event during skeletal muscle hypertrophy and precedes muscle protein accretion. Signaling via mTOR is crucial for ribosome production and hypertrophy; however, the mechanisms by which it regulates these processes remain to be identified. Herein, we investigated the activation of mTOR signaling in hypertrophying myotubes and determined that mTOR coordinates various aspects of gene expression important for ribosome production. First, inhibition of translation with cycloheximide had a more potent effect on protein synthesis than rapamycin indicating that mTOR function during hypertrophy is not on general, but rather on specific protein synthesis. Second, blocking Pol II transcription had a similar effect as Rapamycin and, unexpectedly, revealed the necessity of Pol II transcription for Pol I transcription, suggesting that mTOR may regulate ribosome production also by controlling Class II genes at the transcriptional level. Third, Pol I activity is essential for rDNA transcription and, surprisingly, for protein synthesis as selective Pol I inhibition blunted rDNA transcription, protein synthesis, and the hypertrophic response of myotubes. Finally, mTOR has nuclear localization in muscle, which is not sensitive to rapamycin. Inhibition of mTOR signaling by rapamycin disrupted mTOR-rDNA promoter interaction and resulted in altered histone marks indicative of repressed transcription and formation of higher-order chromatin structure. Thus mTOR signaling appears to regulate muscle hypertrophy by affecting protein synthesis, Class I and II gene expression, and chromatin remodeling.
authors: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: Ferdinand
authors: F
authors: von Walden
authors: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: Chang
authors: C
authors: Liu
authors: Noll Laboratory, Department of Kinesiology and Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania; and.
authors: Nicole
authors: N
authors: Aurigemma
authors: Noll Laboratory, Department of Kinesiology and Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania; and gan11@psu.edu.|Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors: Gustavo A
authors: GA
authors: Nader
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004275:DNA, Ribosomal / Q000235:genetics*; D006984:Hypertrophy / Q000235:genetics; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012270:Ribosomes / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D004275:DNA, Ribosomal; D009124:Muscle Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: RNA Pol I; epigenetics; hypertrophy; mTOR; ribosome biogenesis; transcription