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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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Related in: MedlinePlus

SGK1 protects against starvation-induced muscle atrophyH&E staining of tibialis anterior sections reveals no changes in muscle architecture (scale bar 90 µm).Morphometric analysis demonstrates a decrease in muscle fiber size of the wild-type control mice compared with sgk1tg transgenic littermates (p = 0.0015).Western blot and densitometry analysis shows that levels of phosphorylated Foxo3a at S315 and T32 are increased in sgk1tg.
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fig06: SGK1 protects against starvation-induced muscle atrophyH&E staining of tibialis anterior sections reveals no changes in muscle architecture (scale bar 90 µm).Morphometric analysis demonstrates a decrease in muscle fiber size of the wild-type control mice compared with sgk1tg transgenic littermates (p = 0.0015).Western blot and densitometry analysis shows that levels of phosphorylated Foxo3a at S315 and T32 are increased in sgk1tg.

Mentions: To test whether increased expression of SGK1 was sufficient to protect skeletal muscle against the catabolic stress of starvation, transgenic mice were fasted for 48 h. Remarkably, caSGK1 transgenic mice were protected against starvation-induced decrease in muscle fiber size when compared to age-matched littermate controls (Fig 6A and B). Previous biochemical analyses of fasted mice have shown decreased levels of phosphorylated Foxo3a, which promotes muscle atrophy via increased protein degradation and autophagy (Grumati et al, 2010; Mammucari et al, 2007). Our analyses demonstrated no measurable difference of phosphorylated Foxo3a at S253, but we found a significant increase of phosphorylated Foxo3a at S315 and T32 in starved mice overexpressing SGK1 (Fig 6C). We subsequently analysed gene expression levels of atrogin-1, MuRF-1 and Map1/LC3B by real-time PCR. Expression of atrogin-1 and MuRF-1 increased in wild-type and caSGK1 mice after starvation; however atrogin-1 levels in caSGK1 transgenic mice were significantly lower compared with wild-type. Wild-type mice had a significant increase in Map1/LC3B expression after fasting, which was not observed in caSGK1 transgenic mice (Supporting Information Fig S5A). Furthermore, starved caSGK1 transgenic mice showed a significantly smaller increase in the protein level of autophagy markers such as beclin-1 and LC3B-II when compared to fasted littermates control animals (Supporting Information Fig S5B). Given that autophagy has been implicated in loss of muscle mass during catabolic stress (Mammucari et al, 2007), our results indicate that inhibition of excessive autophagy contributes to the protection of starvation-induced loss of muscle mass in caSGK1 transgenic mice.


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 protects against starvation-induced muscle atrophyH&E staining of tibialis anterior sections reveals no changes in muscle architecture (scale bar 90 µm).Morphometric analysis demonstrates a decrease in muscle fiber size of the wild-type control mice compared with sgk1tg transgenic littermates (p = 0.0015).Western blot and densitometry analysis shows that levels of phosphorylated Foxo3a at S315 and T32 are increased in sgk1tg.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: SGK1 protects against starvation-induced muscle atrophyH&E staining of tibialis anterior sections reveals no changes in muscle architecture (scale bar 90 µm).Morphometric analysis demonstrates a decrease in muscle fiber size of the wild-type control mice compared with sgk1tg transgenic littermates (p = 0.0015).Western blot and densitometry analysis shows that levels of phosphorylated Foxo3a at S315 and T32 are increased in sgk1tg.
Mentions: To test whether increased expression of SGK1 was sufficient to protect skeletal muscle against the catabolic stress of starvation, transgenic mice were fasted for 48 h. Remarkably, caSGK1 transgenic mice were protected against starvation-induced decrease in muscle fiber size when compared to age-matched littermate controls (Fig 6A and B). Previous biochemical analyses of fasted mice have shown decreased levels of phosphorylated Foxo3a, which promotes muscle atrophy via increased protein degradation and autophagy (Grumati et al, 2010; Mammucari et al, 2007). Our analyses demonstrated no measurable difference of phosphorylated Foxo3a at S253, but we found a significant increase of phosphorylated Foxo3a at S315 and T32 in starved mice overexpressing SGK1 (Fig 6C). We subsequently analysed gene expression levels of atrogin-1, MuRF-1 and Map1/LC3B by real-time PCR. Expression of atrogin-1 and MuRF-1 increased in wild-type and caSGK1 mice after starvation; however atrogin-1 levels in caSGK1 transgenic mice were significantly lower compared with wild-type. Wild-type mice had a significant increase in Map1/LC3B expression after fasting, which was not observed in caSGK1 transgenic mice (Supporting Information Fig S5A). Furthermore, starved caSGK1 transgenic mice showed a significantly smaller increase in the protein level of autophagy markers such as beclin-1 and LC3B-II when compared to fasted littermates control animals (Supporting Information Fig S5B). Given that autophagy has been implicated in loss of muscle mass during catabolic stress (Mammucari et al, 2007), our results indicate that inhibition of excessive autophagy contributes to the protection of starvation-induced loss of muscle mass in caSGK1 transgenic mice.

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