title: β-Hydroxy-β-methylbutyrate (HMB) normalizes dexamethasone-induced autophagy-lysosomal pathway in skeletal muscle.
abstract: Dexamethasone-induced muscle atrophy is due to an increase in protein breakdown and a decrease in protein synthesis, associated with an over-stimulation of the autophagy-lysosomal pathway. These effects are mediated by alterations in IGF-1 and PI3K/Akt signaling. In this study, we have investigated the effects of β-Hydroxy-β-methylbutyrate (HMB) on the regulation of autophagy and proteosomal systems. Rats were treated during 21 days with dexamethasone as a model of muscle atrophy. Co-administration of HMB attenuated the effects promoted by dexamethasone. HMB ameliorated the loss in body weight, lean mass and the reduction of the muscle fiber cross-sectional area (shrinkage) in gastrocnemius muscle. Consequently, HMB produced an improvement in muscle strength in the dexamethasone-treated rats. To elucidate the molecular mechanisms responsible for these effects, rat L6 myotubes were used. In these cells, HMB significantly attenuated lysosomal proteolysis induced by dexamethasone by normalizing the changes observed in autophagosome formation, LC3 II, p62 and Bnip3 expression after dexamethasone treatment. HMB effects were mediated by an increase in FoxO3a phosphorylation and concomitant decrease in FoxO transcriptional activity. The HMB effect was due to the restoration of Akt signaling diminished by dexamethasone treatment. Moreover, HMB was also involved in the regulation of the activity of ubiquitin and expression of MurF1 and Atrogin-1, components of the proteasome system that are activated or up-regulated by dexamethasone. In conclusion, in vivo and in vitro studies suggest that HMB exerts protective effects against dexamethasone-induced muscle atrophy by normalizing the Akt/FoxO axis that controls autophagy and ubiquitin proteolysis.
authors: Department of Biochemistry and Molecular Biology II, University of Granada, Granada, Spain.
authors: María D
authors: MD
authors: Girón
authors: Department of Biochemistry and Molecular Biology II, University of Granada, Granada, Spain.
authors: Jose D
authors: JD
authors: Vílchez
authors: Abbott Nutrition R&D, Singapore, Singapore.
authors: Sathyavageeswaran
authors: S
authors: Shreeram
authors: Department of Biochemistry and Molecular Biology II, University of Granada, Granada, Spain.
authors: Rafael
authors: R
authors: Salto
authors: Abbott Nutrition R&D, Granada, Spain.
authors: Manuel
authors: M
authors: Manzano
authors: Department of Biochemistry and Molecular Biology II, University of Granada, Granada, Spain.
authors: Elena
authors: E
authors: Cabrera
authors: Abbott Nutrition R&D, Granada, Spain.
authors: Nefertiti
authors: N
authors: Campos
authors: Abbott Nutrition R&D, Columbus, Ohio, United States of America.
authors: Neile K
authors: NK
authors: Edens
authors: Abbott Nutrition R&D, Granada, Spain.
authors: Ricardo
authors: R
authors: Rueda
authors: Abbott Nutrition R&D, Granada, Spain.
authors: Jose M
authors: JM
authors: López-Pedrosa
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009133:Muscular Atrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014631:Valerates / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D005938:Glucocorticoids; D014631:Valerates; C004961:beta-hydroxyisovaleric acid; D003907:Dexamethasone; D046988:Proteasome Endopeptidase Complex