title: Atomoxetine prevents dexamethasone-induced skeletal muscle atrophy in mice.
abstract: Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. β2-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC-1α) isoforms, ATP synthase β, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 β subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naïve mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1α-4-IGF1-Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1α expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.R.J., M.C.K., K.A.R., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Sean R
authors.initials: SR
authors.lastname: Jesinkey
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.R.J., M.C.K., K.A.R., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Midhun C
authors.initials: MC
authors.lastname: Korrapati
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.R.J., M.C.K., K.A.R., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Rasbach
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.R.J., M.C.K., K.A.R., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.R.J., M.C.K., K.A.R., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.) schnell@musc.edu.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D000818:Animals; D000069445:Atomoxetine Hydrochloride; D003907:Dexamethasone / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D003907:Dexamethasone