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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/34914

Title: β-Hydroxy-β-Methylbutyrate (HMB) Normalizes Dexamethasone-Induced Autophagy-Lysosomal Pathway in Skeletal Muscle
Authors: Girón González, María Dolores
Vílchez Rienda, José Dámaso
Shreeram, Sathyavageeswaran
Salto González, Rafael
Manzano, Manuel
Cabrera, Elena
Campos, Nefertiti
Edens, Neile K.
Rueda Cabrera, Ricardo
López-Pedrosa, José M.
Issue Date: 2015
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.
Sponsorship: This project has been funded by Abbott Nutrition R&D.
Publisher: Public Library of Science (PLOS)
Keywords: Autophagic cell death
Atrophy
Skeletal muscles
Muscle proteins
Proteolysis
Phosphorylation
Muscle biochemistry
Body weight
URI: http://hdl.handle.net/10481/34914
ISSN: 1932-6203
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Girón González, M.D.; et al. β-Hydroxy-β-Methylbutyrate (HMB) Normalizes Dexamethasone-Induced Autophagy-Lysosomal Pathway in Skeletal Muscle. Plos One, 10(2): e0117520 (2015). [http://hdl.handle.net/10481/34914]
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