Glucocorticoids (GCs) are prescribed for their anti-inflammatory and immunosuppressive properties. However, they have significant side-effects including a decline in muscle mass and function which has similarities to age related sacropaenia. Within skeletal muscle 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts 11-dehydrocorticosterone (11DHC) to active corticosterone (CORT) amplifying local GC action. We hypothesise that 11β-HSD1 mediated intramyocellular GC generation may contribute to sarcopenia. To investigate this we assessed 6-week-old male wild-type (WT) mice treated with CORT (100 μg/ml), 11DHC (100 μg/ml) or vehicle via the drinking water for 5 weeks, and young (26 weeks) and aged (112 weeks) WT and 11β-HSD1KO mice and assessed grip strength as a marker of muscle function and assessed muscle gene expression profiles using fluidigm expression arrays.
In WT mice, both CORT and 11DHC increased the expression of the key muscle atrophy genes including the FOXO1&3 transcription factors, MuRF1, atrogin-1, myostatin, GSK3β and GADD45a in quadriceps muscles. This was paralleled by decreased quadriceps weight and grip strength compared to vehicle treated and young mice. WT mice at 112 weeks of age also demonstrated increased expression of the same atrophy gene expression profile in quadriceps muscles as seen in CORT treated mice, paralleled by an age-dependent decrease in grip strength. However, aged 11β-HSD1KO mice were protected from the atrophy associated gene expression profile of increased FOXO1&3, MuRF1, atrogin-1, myostatin, and GSK3β expression, and crucially these mice retained a muscle mass and grip strength reminiscent of a younger mouse.
In summary, we have identified a muscle gene expression profile common to both GC and age associated myopathy, which 11β-HSD1KO mice do not display associated with increased muscle mass and function. These data suggest that muscle expression of 11β-HSD1 could offer a novel therapeutic target preventing GC-related myopathy and sarcopaenia, ultimately improving healthy lifespan.
Declaration of funding
This work was supported by the European Research Council (grant number 20092506).