Preclinical Characterization Of The Jak/Stat Inhibitor Sgi-1252 On Skeletal Muscle Function, Morphology, And Satellite Cell Content

BackgroundRecent studies have highlighted the JAK/STAT signaling pathway in the regulation of muscle satellite cell behavior. Herein we report preclinical studies designed to characterize the effects of a novel JAK/STAT inhibitor on plantar flexor skeletal muscle function, morphology, and satellite cell content.MethodsThe compound, SGI-1252, was administered orally (400mg/kg) in a 10% dextrose solution to wild type mice (n = 6) 3 times per week for 8 weeks. A control group (n = 6) received only the dextrose solution.ResultsSGI-1252 was well tolerated, as animals displayed similar weight gain over the 8-week treatment period. Following treatment, fatigue in the gastrocnemius-soleus-plantaris complex was greater in the SGI-1252 mice during a 300 second tetanic contraction bout (p = 0.035), though both the rate of fatigue and maximal force production were similar. SGI-1252 treated mice had increased type II myofiber cross-sectional area (1434.8 +/- 225.4 vs 1754.7 +/- 138.5 mu m(2)), along with an increase in wet muscle mass (125.45 +/- 5.46 vs 139.6 +/- 12.34 mg, p = 0.032) of the gastrocnemius relative to vehicle treated mice. SGI-1252 treatment reduced gastrocnemius STAT3 phosphorylation 53% (94.79 +/- 45.9 vs 44.5 +/- 6.1 MFI) and significantly increased the concentration of Pax7+ satellite cells (2589.2 +/- 105.5 vs 2859.4 177.5 SC/mm(3)) in the gastrocnemius. SGI-1252 treatment suppressed MyoD (p = 0.013) and Myogenin (p<0.0001) expression in human primary myoblasts, resulting in reduced myogenic differentiation (p = 0.039).ConclusionsOrally delivered SG1-1252 was well tolerated, attenuates skeletal muscle STAT3 activity, and increases satellite cell content in mouse gastrocnemius muscle, likely by inhibiting myogenic progression.