title: The RNA editor gene ADAR1 is induced in myoblasts by inflammatory ligands and buffers stress response.
abstract: Muscle atrophy remains a significant concern in multiple inflammatory conditions, including injury, sepsis, cachexia, and HIV-associated wasting. Herein, we show that inflammatory stressors, including TNF-alpha, IFN-gamma, or lipopolysaccharide, potently induced the novel expression of the RNA editor ADAR1, an observation not previously described in muscle cells. We also observed that cytokine stimulation suppressed muscle-associated microRNAs, an observation also not previously demonstrated. To map potential effects of ADAR1 induction in the muscle program, we conducted knockdown and overexpression studies in the mouse C2C12 muscle precursor cell (MPC) line and in primary human MPCs. We show that knockdown of stress-induced ADAR1 increased inflammation-mediated declines in the muscle differentiation markers Myogenin and myosin heavy chain, and knockdown reduced levels of active phosphorylated Akt (phospho-Akt), but had no effect on microRNA transcript levels, suggesting a role for ADAR1 in buffering inflammatory stress effects on myogenic transcription and protein synthesis pathways. In addition, overexpression of recombinant ADAR1 suppressed active phosphorylated double-stranded RNA (dsRNA)-dependent protein kinase (phospho-PKR), consistent with a role for ADAR1 in limiting inflammation-driven catabolic atrophy pathways. Collectively, these data identify a novel regulatory role for ADAR1 activation under inflammatory stress to both promote muscle protein synthesis pathways and limit atrophy pathways.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Micah
authors.initials: M
authors.lastname: Meltzer
authors.forename: Kimberly
authors.initials: K
authors.lastname: Long
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Mayetri
authors.initials: M
authors.lastname: Gupta
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yang
authors.forename: Monty
authors.initials: M
authors.lastname: Montano
mesh_terms: D000243:Adenosine Deaminase / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004790:Enzyme Induction; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics; D008024:Ligands; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D032342:Muscle Cells / Q000166:cytology / Q000201:enzymology; D024510:Muscle Development / Q000235:genetics; D032446:Myoblasts / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017393:RNA Editing / Q000235:genetics*; D016601:RNA-Binding Proteins; D013312:Stress, Physiological / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D016207:Cytokines; D008024:Ligands; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D051057:Proto-Oncogene Proteins c-akt; D019892:eIF-2 Kinase; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase