Limits...
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.

Show MeSH

Related in: MedlinePlus

SGK1 in skeletal muscle is critical for preservation of skeletal muscleWestern blot analyses and densitometry of quadriceps muscles from non-hibernating and hibernating squirrels demonstrates significant increases in total SGK1 and phosphorylated SGK1. Immunostaining of quadriceps muscle for total SGK1 shows upregulation during hibernation.Levels of phosphorylated Foxo3a in S315 and T32 are significantly increased during hibernation. Densitometric analysis of P-Foxo3a as a function of Foxo3a.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3569655&req=5

fig03: SGK1 in skeletal muscle is critical for preservation of skeletal muscleWestern blot analyses and densitometry of quadriceps muscles from non-hibernating and hibernating squirrels demonstrates significant increases in total SGK1 and phosphorylated SGK1. Immunostaining of quadriceps muscle for total SGK1 shows upregulation during hibernation.Levels of phosphorylated Foxo3a in S315 and T32 are significantly increased during hibernation. Densitometric analysis of P-Foxo3a as a function of Foxo3a.

Mentions: Serum- and glucocorticoid-inducible kinase 1 (SGK1) is a downstream target of the IGF-1/PDK-1 signalling cascade and shares a similar consensus phosphorylation site (RXRXXS/T) with Akt. Additionally, SGK1 phosphorylates Foxo3a at serine-253, serine-315 (S315) and T32 (Brunet et al, 2001) and is an alternative regulator of mTOR-mediated cell growth and survival in non-muscle cells (Aoyama et al, 2005). Therefore, we analysed SGK1 protein levels in the skeletal muscle of summer and hibernating squirrels. Hibernating muscles exhibited a significant increase in total and phosphorylated SGK1 that decreased to pre-hibernation levels once the animals emerged from torpor (Fig 3A). Immunostaining also showed increased SGK1 expression in hibernation (Fig 3A). As expected, increased phosphorylation of Foxo3a at S315 and T32 accompanied increase in levels of total and activated SGK1 (Fig 3B). Co-immunostaining revealed SGK1 localized mainly in fast, type II muscle fibers, which play a critical role in force generation during contractile activity (Supporting Information Fig S2A). In addition, cytoplasmic co-localization of SGK1 with phosphorylated Foxo3a (S253) was detected in type II muscle fibers of hibernating squirrels (Supporting Information Fig S2A) supporting our hypothesis that SGK1 modulates the inhibition of Foxo3a.


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)

SGK1 in skeletal muscle is critical for preservation of skeletal muscleWestern blot analyses and densitometry of quadriceps muscles from non-hibernating and hibernating squirrels demonstrates significant increases in total SGK1 and phosphorylated SGK1. Immunostaining of quadriceps muscle for total SGK1 shows upregulation during hibernation.Levels of phosphorylated Foxo3a in S315 and T32 are significantly increased during hibernation. Densitometric analysis of P-Foxo3a as a function of Foxo3a.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: SGK1 in skeletal muscle is critical for preservation of skeletal muscleWestern blot analyses and densitometry of quadriceps muscles from non-hibernating and hibernating squirrels demonstrates significant increases in total SGK1 and phosphorylated SGK1. Immunostaining of quadriceps muscle for total SGK1 shows upregulation during hibernation.Levels of phosphorylated Foxo3a in S315 and T32 are significantly increased during hibernation. Densitometric analysis of P-Foxo3a as a function of Foxo3a.
Mentions: Serum- and glucocorticoid-inducible kinase 1 (SGK1) is a downstream target of the IGF-1/PDK-1 signalling cascade and shares a similar consensus phosphorylation site (RXRXXS/T) with Akt. Additionally, SGK1 phosphorylates Foxo3a at serine-253, serine-315 (S315) and T32 (Brunet et al, 2001) and is an alternative regulator of mTOR-mediated cell growth and survival in non-muscle cells (Aoyama et al, 2005). Therefore, we analysed SGK1 protein levels in the skeletal muscle of summer and hibernating squirrels. Hibernating muscles exhibited a significant increase in total and phosphorylated SGK1 that decreased to pre-hibernation levels once the animals emerged from torpor (Fig 3A). Immunostaining also showed increased SGK1 expression in hibernation (Fig 3A). As expected, increased phosphorylation of Foxo3a at S315 and T32 accompanied increase in levels of total and activated SGK1 (Fig 3B). Co-immunostaining revealed SGK1 localized mainly in fast, type II muscle fibers, which play a critical role in force generation during contractile activity (Supporting Information Fig S2A). In addition, cytoplasmic co-localization of SGK1 with phosphorylated Foxo3a (S253) was detected in type II muscle fibers of hibernating squirrels (Supporting Information Fig S2A) supporting our hypothesis that SGK1 modulates the inhibition of Foxo3a.

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