Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy.
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.
Affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.Show MeSH
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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.
Affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.