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Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy.

Andres-Mateos E, Brinkmeier H, Burks TN, Mejias R, Files DC, Steinberger M, Soleimani A, Marx R, Simmers JL, Lin B, Finanger Hedderick E, Marr TG, Lin BM, Hourdé C, Leinwand LA, Kuhl D, Föller M, Vogelsang S, Hernandez-Diaz I, Vaughan DK, Alvarez de la Rosa D, Lang F, Cohn RD - EMBO Mol Med (2012)

Bottom Line: Here, we describe a mechanism underlying muscle preservation and translate it to non-hibernating mammals.Although Akt has an established role in skeletal muscle homeostasis, we find that serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates muscle mass maintenance via downregulation of proteolysis and autophagy as well as increased protein synthesis during hibernation.Our results identify a novel therapeutic target to combat loss of skeletal muscle mass associated with muscle degeneration and atrophy.

View Article: PubMed Central - PubMed

Affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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Evaluation of protein degradation and synthesis pathwaysWestern blot of quadriceps muscle from summer active (S) and hibernating (H) squirrels using antibodies against the proteins indicated. An increased abundance of P-Foxo3a (serine-253) is accompanied by a decrease in P-Akt (serine-478). Corresponding densitometry of P-Akt and P-Foxo3a as a function of total Akt and Foxo3a.Relative mRNA levels for four Foxo3a downstream targets show no significant changes during hibernation.Western blots analysis of mTOR downstream targets shows significant upregulation of P-P70S6K and P-4E-BP1 during hibernation.
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fig02: Evaluation of protein degradation and synthesis pathwaysWestern blot of quadriceps muscle from summer active (S) and hibernating (H) squirrels using antibodies against the proteins indicated. An increased abundance of P-Foxo3a (serine-253) is accompanied by a decrease in P-Akt (serine-478). Corresponding densitometry of P-Akt and P-Foxo3a as a function of total Akt and Foxo3a.Relative mRNA levels for four Foxo3a downstream targets show no significant changes during hibernation.Western blots analysis of mTOR downstream targets shows significant upregulation of P-P70S6K and P-4E-BP1 during hibernation.

Mentions: The PI3K/Akt/mTOR pathway stimulates myofiber growth and protein synthesis and regulates protein degradation (Bodine et al, 2001). We assessed members of this pathway in skeletal muscle of hibernating and non-hibernating animals. Levels of phosphorylated (inactive) Foxo3a at serine-253 were increased (Fig 2A). Evaluation of downstream targets of Foxo3a by real-time PCR revealed no significant increase in expression of atrophy or autophagy genes including atrogin-1 and MuRF1 or MAP1/LC3B during hibernation (Fig 2B). Analysis of the proteasome during hibernation showed an elevation of ubiquitinated proteins (Supporting Information Fig S1F) and proteasome activity was not increased (Supporting Information Fig S1C). In addition, increased levels of p62/SQSTM1 and a decreased ratio of LC3B-II/LC3B-I during hibernation indicated suppression of autophagy (Supporting Information Fig S1D and E).


Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy.

Andres-Mateos E, Brinkmeier H, Burks TN, Mejias R, Files DC, Steinberger M, Soleimani A, Marx R, Simmers JL, Lin B, Finanger Hedderick E, Marr TG, Lin BM, Hourdé C, Leinwand LA, Kuhl D, Föller M, Vogelsang S, Hernandez-Diaz I, Vaughan DK, Alvarez de la Rosa D, Lang F, Cohn RD - EMBO Mol Med (2012)

Evaluation of protein degradation and synthesis pathwaysWestern blot of quadriceps muscle from summer active (S) and hibernating (H) squirrels using antibodies against the proteins indicated. An increased abundance of P-Foxo3a (serine-253) is accompanied by a decrease in P-Akt (serine-478). Corresponding densitometry of P-Akt and P-Foxo3a as a function of total Akt and Foxo3a.Relative mRNA levels for four Foxo3a downstream targets show no significant changes during hibernation.Western blots analysis of mTOR downstream targets shows significant upregulation of P-P70S6K and P-4E-BP1 during hibernation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569655&req=5

fig02: Evaluation of protein degradation and synthesis pathwaysWestern blot of quadriceps muscle from summer active (S) and hibernating (H) squirrels using antibodies against the proteins indicated. An increased abundance of P-Foxo3a (serine-253) is accompanied by a decrease in P-Akt (serine-478). Corresponding densitometry of P-Akt and P-Foxo3a as a function of total Akt and Foxo3a.Relative mRNA levels for four Foxo3a downstream targets show no significant changes during hibernation.Western blots analysis of mTOR downstream targets shows significant upregulation of P-P70S6K and P-4E-BP1 during hibernation.
Mentions: The PI3K/Akt/mTOR pathway stimulates myofiber growth and protein synthesis and regulates protein degradation (Bodine et al, 2001). We assessed members of this pathway in skeletal muscle of hibernating and non-hibernating animals. Levels of phosphorylated (inactive) Foxo3a at serine-253 were increased (Fig 2A). Evaluation of downstream targets of Foxo3a by real-time PCR revealed no significant increase in expression of atrophy or autophagy genes including atrogin-1 and MuRF1 or MAP1/LC3B during hibernation (Fig 2B). Analysis of the proteasome during hibernation showed an elevation of ubiquitinated proteins (Supporting Information Fig S1F) and proteasome activity was not increased (Supporting Information Fig S1C). In addition, increased levels of p62/SQSTM1 and a decreased ratio of LC3B-II/LC3B-I during hibernation indicated suppression of autophagy (Supporting Information Fig S1D and E).

Bottom Line: Here, we describe a mechanism underlying muscle preservation and translate it to non-hibernating mammals.Although Akt has an established role in skeletal muscle homeostasis, we find that serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates muscle mass maintenance via downregulation of proteolysis and autophagy as well as increased protein synthesis during hibernation.Our results identify a novel therapeutic target to combat loss of skeletal muscle mass associated with muscle degeneration and atrophy.

View Article: PubMed Central - PubMed

Affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Show MeSH
Related in: MedlinePlus