RT Journal Article
SR Electronic
T1 Atomoxetine prevents dexamethasone-induced skeletal muscle atrophy in mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.114.217380
DO 10.1124/jpet.114.217380
A1 Sean R. Jesinkey
A1 Midhun Korrapati
A1 Kyle A. Rasbach
A1 Craig C. Beeson
A1 Rick G. Schnellmann
YR 2014
UL http://jpet.aspetjournals.org/content/early/2014/10/07/jpet.114.217380.abstract
AB Skeletal muscle atrophy remains a clinical problem in numerous pathological 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 dexamethasoneinduced 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 h or 8 days later. Gastrocnemius muscle weights; changes in mRNA and protein expression of PGC-1α isoforms, ATP synthase β, Cox 1, NDUFB8, and ND1, IGF-1, myostatin, MuRF-1 (muscle atrophy), phosphorylated (p)-FoxO3a, Akt, mTOR, and rp-S6 (muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 h after treatment in naive mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1α4-IGF1-Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 h and repressed myostatin at 16 h. In contrast to what was observed with acute treatment, chronic treatment (7-days) with atomoxetine increased p-Akt, 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.