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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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Sgk1−/− mice exhibit decreased muscle fiber size and impaired muscle functionThe morphology of tibialis anterior muscle as revealed by haematoxylin–eosin staining shows increased variation in muscle fiber size with numerous atrophic muscle fibers (scale bar 90 µm).Percentage distribution and mean minimum Feret's diameter in tibialis anterior muscle (p = 0.02).Increased levels of phosphorylated Akt (S478) in skeletal muscles of sgk1−/− mice.sgk1−/− mice exhibit decreased running distance after 36 days of exposure to a running wheel, (p = 0.01; n = 6 animals per group).Isometric force from soleus muscles of WT and sgk1−/− mice during repetitive electrical stimulations for 500 ms. Amplitudes of isometric force from soleus muscles at two stimulation frequencies. Specific force is plotted in all cases. Mean values ± SD from n = 9 (sgk1−/−) and n = 10 (WT) independent animals (p = 0.01).
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fig04: Sgk1−/− mice exhibit decreased muscle fiber size and impaired muscle functionThe morphology of tibialis anterior muscle as revealed by haematoxylin–eosin staining shows increased variation in muscle fiber size with numerous atrophic muscle fibers (scale bar 90 µm).Percentage distribution and mean minimum Feret's diameter in tibialis anterior muscle (p = 0.02).Increased levels of phosphorylated Akt (S478) in skeletal muscles of sgk1−/− mice.sgk1−/− mice exhibit decreased running distance after 36 days of exposure to a running wheel, (p = 0.01; n = 6 animals per group).Isometric force from soleus muscles of WT and sgk1−/− mice during repetitive electrical stimulations for 500 ms. Amplitudes of isometric force from soleus muscles at two stimulation frequencies. Specific force is plotted in all cases. Mean values ± SD from n = 9 (sgk1−/−) and n = 10 (WT) independent animals (p = 0.01).

Mentions: To further address the role of SGK1 in skeletal muscle maintenance, we evaluated skeletal muscle composition and function in mice lacking sgk1. These mice exhibit impaired renal sodium retention but the muscle phenotype has not been studied (Wulff et al, 2002). Mice deficient for sgk1 showed no changes in body mass but revealed decreased weight of the TA muscles (Supporting Information Fig S2F). Histological evaluation of skeletal muscles of sgk1−/− mice demonstrated increased variation of fiber size with numerous small and rounded myofibers (Fig 4A). Morphometric data confirmed that sgk1−/− mice had decreased muscle fiber size in the TA, gastrocnemius and soleus muscles (Fig 4B and Supporting Information Fig S3E). Fiber type analysis of gastrocnemius and TA muscles did not reveal changes in fiber type composition (Supporting Information Fig S2G). Despite the decrease in muscle fiber size, skeletal muscle of sgk1−/− mice showed an increase in phosphorylated Akt (Fig 4C and Supporting Information Fig S3A). Levels of phosphorylated Foxo3a at S315 were decreased in sgk1−/− mice, whereas levels of phospho-Foxo3a at S253, LC3B and p62 were unchanged (Supporting Information Fig S3B).


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−/− mice exhibit decreased muscle fiber size and impaired muscle functionThe morphology of tibialis anterior muscle as revealed by haematoxylin–eosin staining shows increased variation in muscle fiber size with numerous atrophic muscle fibers (scale bar 90 µm).Percentage distribution and mean minimum Feret's diameter in tibialis anterior muscle (p = 0.02).Increased levels of phosphorylated Akt (S478) in skeletal muscles of sgk1−/− mice.sgk1−/− mice exhibit decreased running distance after 36 days of exposure to a running wheel, (p = 0.01; n = 6 animals per group).Isometric force from soleus muscles of WT and sgk1−/− mice during repetitive electrical stimulations for 500 ms. Amplitudes of isometric force from soleus muscles at two stimulation frequencies. Specific force is plotted in all cases. Mean values ± SD from n = 9 (sgk1−/−) and n = 10 (WT) independent animals (p = 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Sgk1−/− mice exhibit decreased muscle fiber size and impaired muscle functionThe morphology of tibialis anterior muscle as revealed by haematoxylin–eosin staining shows increased variation in muscle fiber size with numerous atrophic muscle fibers (scale bar 90 µm).Percentage distribution and mean minimum Feret's diameter in tibialis anterior muscle (p = 0.02).Increased levels of phosphorylated Akt (S478) in skeletal muscles of sgk1−/− mice.sgk1−/− mice exhibit decreased running distance after 36 days of exposure to a running wheel, (p = 0.01; n = 6 animals per group).Isometric force from soleus muscles of WT and sgk1−/− mice during repetitive electrical stimulations for 500 ms. Amplitudes of isometric force from soleus muscles at two stimulation frequencies. Specific force is plotted in all cases. Mean values ± SD from n = 9 (sgk1−/−) and n = 10 (WT) independent animals (p = 0.01).
Mentions: To further address the role of SGK1 in skeletal muscle maintenance, we evaluated skeletal muscle composition and function in mice lacking sgk1. These mice exhibit impaired renal sodium retention but the muscle phenotype has not been studied (Wulff et al, 2002). Mice deficient for sgk1 showed no changes in body mass but revealed decreased weight of the TA muscles (Supporting Information Fig S2F). Histological evaluation of skeletal muscles of sgk1−/− mice demonstrated increased variation of fiber size with numerous small and rounded myofibers (Fig 4A). Morphometric data confirmed that sgk1−/− mice had decreased muscle fiber size in the TA, gastrocnemius and soleus muscles (Fig 4B and Supporting Information Fig S3E). Fiber type analysis of gastrocnemius and TA muscles did not reveal changes in fiber type composition (Supporting Information Fig S2G). Despite the decrease in muscle fiber size, skeletal muscle of sgk1−/− mice showed an increase in phosphorylated Akt (Fig 4C and Supporting Information Fig S3A). Levels of phosphorylated Foxo3a at S315 were decreased in sgk1−/− mice, whereas levels of phospho-Foxo3a at S253, LC3B and p62 were unchanged (Supporting Information Fig S3B).

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