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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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Characterization of skeletal muscle of SGK1 transgenic miceH&E staining of tibialis anterior sections from 2-month old control and transgenic mice shows no differences (scale bar 90 µm).Morphometric analyses of minimum Feret's diameter of TA muscle reveal no changes in fiber size distribution or mean fiber size.Western blots and densitometric analysis of muscle from transgenic and control mice. Downstream targets of the mTOR signalling cascade (p70S6K and 4EBP1) demonstrate significant upregulation of their phosphorylated forms in sgk1tg mice.Western blot analyses and densitometry of phosphorylated FOXO3a and total FOXO3a of tibialis anterior muscles from control and transgenic mice (n = 4) show an increase of phosphorylation at S315 and T32.
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fig05: Characterization of skeletal muscle of SGK1 transgenic miceH&E staining of tibialis anterior sections from 2-month old control and transgenic mice shows no differences (scale bar 90 µm).Morphometric analyses of minimum Feret's diameter of TA muscle reveal no changes in fiber size distribution or mean fiber size.Western blots and densitometric analysis of muscle from transgenic and control mice. Downstream targets of the mTOR signalling cascade (p70S6K and 4EBP1) demonstrate significant upregulation of their phosphorylated forms in sgk1tg mice.Western blot analyses and densitometry of phosphorylated FOXO3a and total FOXO3a of tibialis anterior muscles from control and transgenic mice (n = 4) show an increase of phosphorylation at S315 and T32.

Mentions: Next, we analysed skeletal muscle of transgenic mice overexpressing the sgk1 gene, which was modified by a point mutation (S422D) that renders the kinase constitutively active (Kobayashi & Cohen, 1999). RT-PCR analyses of the TA demonstrated an approximate 30% increase in expression of SGK1, which, in the context of the constitutively active kinase, provides an estimated threefold increase of SGK1 activation (Supporting Information Fig S4A and B). Histological and morphometric analyses of several skeletal muscles revealed no significant difference between the two groups (Fig 5A and B and Supporting Information Fig S4C). Interestingly, transgenic mice with inducible overexpression of Akt develop muscular abnormalities after Akt was induced and active during 6 months (Grumati et al, 2010), while constitutively active (ca)SGK1 transgenic adult mice did not show any pathological abnormalities at this age (Supporting Information Fig S4D). Fiber type immunostaining in gastrocnemius and TA muscles did not reveal changes in fiber type composition (Supporting Information Fig S4E). Biochemical analyses demonstrated increased abundance of phosphorylated p70S6K and 4E-BP1 (Fig 5C). Furthermore, skeletal muscle of caSGK1 transgenic mice exhibited increased phosphorylation of Foxo3a at S315 and T32, similar to our findings in hibernating skeletal muscle (Fig 5D). Unexpectedly, analyses of autophagy markers in sgk1 transgenic showed increased basal levels of LC3B-II and p62 (Supporting Information Fig S4F). Overall, our examination of these mice finds that overexpression of SGK1 does not cause any gross abnormal muscle phenotype.


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)

Characterization of skeletal muscle of SGK1 transgenic miceH&E staining of tibialis anterior sections from 2-month old control and transgenic mice shows no differences (scale bar 90 µm).Morphometric analyses of minimum Feret's diameter of TA muscle reveal no changes in fiber size distribution or mean fiber size.Western blots and densitometric analysis of muscle from transgenic and control mice. Downstream targets of the mTOR signalling cascade (p70S6K and 4EBP1) demonstrate significant upregulation of their phosphorylated forms in sgk1tg mice.Western blot analyses and densitometry of phosphorylated FOXO3a and total FOXO3a of tibialis anterior muscles from control and transgenic mice (n = 4) show an increase of phosphorylation at S315 and T32.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Characterization of skeletal muscle of SGK1 transgenic miceH&E staining of tibialis anterior sections from 2-month old control and transgenic mice shows no differences (scale bar 90 µm).Morphometric analyses of minimum Feret's diameter of TA muscle reveal no changes in fiber size distribution or mean fiber size.Western blots and densitometric analysis of muscle from transgenic and control mice. Downstream targets of the mTOR signalling cascade (p70S6K and 4EBP1) demonstrate significant upregulation of their phosphorylated forms in sgk1tg mice.Western blot analyses and densitometry of phosphorylated FOXO3a and total FOXO3a of tibialis anterior muscles from control and transgenic mice (n = 4) show an increase of phosphorylation at S315 and T32.
Mentions: Next, we analysed skeletal muscle of transgenic mice overexpressing the sgk1 gene, which was modified by a point mutation (S422D) that renders the kinase constitutively active (Kobayashi & Cohen, 1999). RT-PCR analyses of the TA demonstrated an approximate 30% increase in expression of SGK1, which, in the context of the constitutively active kinase, provides an estimated threefold increase of SGK1 activation (Supporting Information Fig S4A and B). Histological and morphometric analyses of several skeletal muscles revealed no significant difference between the two groups (Fig 5A and B and Supporting Information Fig S4C). Interestingly, transgenic mice with inducible overexpression of Akt develop muscular abnormalities after Akt was induced and active during 6 months (Grumati et al, 2010), while constitutively active (ca)SGK1 transgenic adult mice did not show any pathological abnormalities at this age (Supporting Information Fig S4D). Fiber type immunostaining in gastrocnemius and TA muscles did not reveal changes in fiber type composition (Supporting Information Fig S4E). Biochemical analyses demonstrated increased abundance of phosphorylated p70S6K and 4E-BP1 (Fig 5C). Furthermore, skeletal muscle of caSGK1 transgenic mice exhibited increased phosphorylation of Foxo3a at S315 and T32, similar to our findings in hibernating skeletal muscle (Fig 5D). Unexpectedly, analyses of autophagy markers in sgk1 transgenic showed increased basal levels of LC3B-II and p62 (Supporting Information Fig S4F). Overall, our examination of these mice finds that overexpression of SGK1 does not cause any gross abnormal muscle phenotype.

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